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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
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Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
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The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee
Alessandro Beghini
Anne von Bergh
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Albert Schinzel
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Solid Tumours Section
Genes Section
Genes / Leukaemia Sections
Solid Tumours Section
Leukaemia Section
Deep Insights Section
Solid Tumours Section
Genes / Deep Insights Sections
Leukaemia Section
Genes / Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia / Solid Tumours Sections
Solid Tumours Section
Solid Tumours Section
Cancer-Prone Diseases / Deep Insights Sections
Cancer-Prone Diseases Section
Genes / Leukaemia Sections
Deep Insights Section
Leukaemia Section
Genes / Deep Insights Sections
Deep Insights Section
Solid Tumours Section
Solid Tumours Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Leukaemia Sections
Cancer-Prone Diseases Section
Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Solid Tumours Sections
Deep Insights Section
Genes / Leukaemia Section
Genes Section
Cancer-Prone Diseases Section
Education Section
Genes Section
Genes / Leukaemia Sections
Genes / Cancer-Prone Diseases Sections
Education Section
Solid Tumours Section
Leukaemia Section
Leukaemia Section
Genes / Leukaemia Sections
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 14, Number 3, March 2010
Table of contents
Gene Section
MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian))
Celio Pouponnot, Alain Eychène
235
MAP3K7 (mitogen-activated protein kinase kinase kinase 7)
Hui Hui Tang, Kam C Yeung
238
MCPH1 (microcephalin 1)
Yulong Liang, Shiaw-Yih Lin, Kaiyi Li
243
NKX3-1 (NK3 homeobox 1)
Liang-Nian Song, Edward P Gelmann
246
PLXNB1 (plexin B1)
José Javier Gómez-Román, Montserrat Nicolas Martínez,
Servando Lazuén Fernández, José Fernando Val-Bernal
249
RUVBL1 (RuvB-like 1 (E. coli))
Valérie Haurie, Aude Grigoletto, Jean Rosenbaum
254
RUVBL2 (RuvB-like 2 (E. coli))
Aude Grigoletto, Valérie Haurie, Jean Rosenbaum
257
SH3GL2 (SH3-domain GRB2-like 2)
Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti
260
TOPORS (topoisomerase I binding, arginine/serine-rich)
Jafar Sharif, Asami Tsuboi, Haruhiko Koseki
263
TRPV6 (transient receptor potential cation channel, subfamily V, member 6)
Yoshiro Suzuki, Matthias A Hediger
267
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))
Shian-Ying Sung
270
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1)
Maria Norlin
275
EPHA3 (EPH receptor A3)
Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd
279
JAZF1 (JAZF zinc finger 1)
Hui Li, Jeffrey Sklar
286
LPAR1 (lysophosphatidic acid receptor 1)
Mandi M Murph, Harish Radhakrishna
289
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide)
Montserrat Sanchez-Cespedes
293
SFRP4 (Secreted Frizzled-Related Protein 4)
Kendra S Carmon, David S Loose
296
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian))
Stephen Hiscox
301
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
t(11;14)(q13;q32)
in multiple myeloma
Atlas
of Genetics
and Cytogenetics
in Oncology and Haematology
Huret JL, Laï JL
OPEN ACCESS JOURNAL AT INIST-CNRS
TACC3 (transforming, acidic coiled-coil containing protein 3)
Melissa R Eslinger, Brenda Lauffart, Ivan H Still
305
TP53INP1 (tumor protein p53 inducible nuclear protein 1)
Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti
311
Leukaemia Section
del(5q) in myeloid neoplasms
Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke
314
t(11;11)(q13;q23)
Jean-Loup Huret
317
t(11;19)(q23;p13.3) MLL/ACER1
Jean-Loup Huret
319
t(2;5)(p21;q33)
Jean-Loup Huret
320
Solid Tumour Section
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Rodney C Diaz
321
Lymphangioleiomyoma
Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss
327
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MAFA (v-maf musculoaponeurotic fibrosarcoma
oncogene homolog A (avian))
Celio Pouponnot, Alain Eychène
Institut Curie, CNRS UMR 146, F-91405 Orsay, France (CP, AE)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MAFAID41235ch8q24.html
DOI: 10.4267/2042/44698
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pseudogene
Identity
Unknown.
Other names: RIPE3b1; KLRG1; Maf-A,: hMafA; LMaf
HGNC (Hugo): MAFA
Location: 8q24.3
Local order: C8orf51, RHPN1, MAFA, ZC3H3,
GSDMD
Protein
Note
Maf oncoproteins are b-ZIP transcription factors that
belong to the AP-1 super-family, which notably
includes JUN and FOS. The Maf family contains seven
members, which can be subdivided into two groups; the
large and small Maf proteins. While the small Maf
proteins, MAFF, MAFG and MAFK, are essentially
composed of a b-Zip domain, the large Maf proteins,
MAFA/L-MAF, MAFB, MAF/c-MAF and NRL
contain an additional amino-terminal transactivation
domain. MAFA was initially cloned in quail and
chicken species and named MAFA and L-MAF,
respectively. More recently, mammalian MAFA was
cloned and identi-fied as an essential component of the
RIPE3b1 complex, which binds the insulin promoter.
DNA/RNA
Note
The MAFA open reading frame is encoded by a unique
exon. The entire genomic organization and the putative
existence of non-coding exons remain unknown.
Transcription
MAFA displays a restricted expression pattern. It is
notably expressed in pancreas (in beta-cells) and lens.
Schematic representation of the MAFA protein structure. Critical residues involved in post-translational modifications are indicated by the
color code. The kinases responsible for S14 and S65 phosphorylation in MAFA remain to be identified. GSK-3 phosphorylates the
transactivation domain of MAFA, thereby inducing its ubiquitination and proteasome-dependent degradation. This is linked to an increase
in MAFA transactivation. These phosphorylations are required for MAFA transforming activity. In contrast, sumoylation of MAFA
transactivation domain decreases its transactivation activity.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
235
MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian))
Description
Implicated in
MAFA, like all large Maf proteins, contains an aminoterminal transactivation domain and a carboxy-terminal
b-ZIP DNA binding domain. Large Maf proteins
stimulate transcription of their target genes through
their binding to two types of palindromic sequences
called TRE- or CRE- type MARE (Maf Responsive
Element) (TGCTGAC(G) TCAGCA). The leucine
zipper domain allows the formation of homo- or heterodimers, an absolute pre-requisite for DNA binding. As
homodimers, these proteins recognize palindromic
sequences, with the basic domain contacting DNA
directly. Among the AP-1 family, the Maf proteins are
defined by the presence of an additional homolo-gous
domain, called the Extended Homology Region (EHR)
or ancillary domain, which also contacts DNA.
Consequently, they recognize a longer palindromic
sequence than other AP-1 family members. The MARE
sequence is composed of a TRE or CRE core contacted
by the basic domain and a TGC flanking sequence,
which is recognized by the EHR domain. While the
TGC motif is crucial for Maf binding, the TRE/CRE
core can be more degenerate. MAFA transactivation
activity and stability is regulated by post-trans-lational
modifications (phosphorylation, ubiquityla-tion and
sumoylation) mostly occuring on the transactivation
domain. GSK-3 was identified as the major protein
kinase regulating MAFA activity and oncogenic
properties.
Multiple myeloma
Hybrid/Mutated gene
Two cases reported translocations of MAFA to the
immunoglobulin heavy-chain (IgH) locus, juxta-posing
the MAFA gene with the strong enhancers of the IgH
locus (meeting report, accurate description lacking).
Oncogenesis
Large Maf proteins, MAFA, MAFB, and MAF/c-MAF
are bona fide oncogenes as demonstrated in tissue
culture, animal models and in human cancers. MAFA
displays the strongest transforming activity, in vitro. In
human, MAF/c-MAF, MAFB and MAFA genes are
translocated to the immunoglo-bulin heavy chain (IgH)
locus in 8-10% of multiple myelomas. MAFA
translocations are present in less than 1% of multiple
myelomas. MAF/C-MAF over-expression plays a
causative role in multiple myeloma by promoting
proliferation and patholo-gical interactions with bone
marrow stroma.
The transforming activity of Maf proteins is context
dependent and they can occasionally display tumor
suppressor-like activity in specific cellular settings.
Their transforming activity relies on overexpression
and does not require an activating mutation (no
activating mutation has been identified to be associated
with human cancers). It is regulated by posttranslational modifications, notably phospho-rylation.
Expression
References
Endogenous MAFA protein is detected and phosphorrylated in pancreatic beta cells.
Benkhelifa S, Provot S, Lecoq O, Pouponnot C, Calothy G,
Felder-Schmittbuhl MP. mafA, a novel member of the maf
proto-oncogene family, displays developmental regulation and
mitogenic capacity in avian neuroretina cells. Oncogene. 1998
Jul 16;17(2):247-54
Localisation
Nucleus.
Function
Ogino H, Yasuda K. Induction of lens differentiation by
activation of a bZIP transcription factor, L-Maf. Science. 1998
Apr 3;280(5360):115-8
During development, Maf proteins are involved early in
specification and later in terminal differen-tiation.
MAFA is involved in the regulation of insulin gene
expression in pancreatic beta cells. Accordingly,
MAFA ablation in mice leads to diabetes.
Besides their roles during development, large Maf
proteins, MAFA, MAFB, and MAF/c-MAF are also
involved in oncogenesis.
Benkhelifa S, Provot S, Nabais E, Eychène A, Calothy G,
Felder-Schmittbuhl MP. Phosphorylation of MafA is essential
for its transcriptional and biological properties. Mol Cell Biol.
2001 Jul;21(14):4441-52
Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H.
MafA is a glucose-regulated and pancreatic beta-cell-specific
transcriptional activator for the insulin gene. J Biol Chem. 2002
Dec 20;277(51):49903-10
Homology
MAFB and MAF/c-MAF are the closest MAFA
homologs. The MAFA entire protein sequence shares
52%, 48% and 40% identity with those of MAFB,
MAF/c-MAF and NRL, respectively. MAFA DNA
binding domain (EHR + b-ZIP) shares 82%, 83%, 64%
and 55-60% identity with those of MAFB, MAF/cMAF, NRL and small MAFs, respectively. MAFA and
JUN share 30% sequence identity in their b-ZIP
domain (20% identity in their entire sequence).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Pouponnot C, Eychène A
Olbrot M, Rud J, Moss LG, Sharma A. Identification of betacell-specific insulin gene transcription factor RIPE3b1 as
mammalian MafA. Proc Natl Acad Sci U S A. 2002 May
14;99(10):6737-42
Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D,
Means A, Stein R. Members of the large Maf transcription
family regulate insulin gene transcription in islet beta cells. Mol
Cell Biol. 2003 Sep;23(17):6049-62
Nishizawa M, Kataoka K, Vogt PK. MafA has strong cell
transforming ability but is a weak transactivator. Oncogene.
2003 Sep 11;22(39):7882-90
236
MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian))
Hanamura I, Iida S, Ueda R, Kuehl M, Cullraro C, Bergsagel L,
Sawyer J, Barlogie B, Shaughnessy Jr J.. Identification of three
novel chromosomal translocation partners involving the
immunoglobulin loci in newly diagnosed myeloma and human
myeloma cell lines. Blood (ASH Annual Meeting Abstracts)
2005; 106:1552.
Pouponnot C, Eychène A
Han SI, Aramata S, Yasuda K, Kataoka K. MafA stability in
pancreatic beta cells is regulated by glucose and is dependent
on its constitutive phosphorylation at multiple sites by glycogen
synthase kinase 3. Mol Cell Biol. 2007 Oct;27(19):6593-605
Rocques N, Abou Zeid N, Sii-Felice K, Lecoin L, FelderSchmittbuhl MP, Eychène A, Pouponnot C. GSK-3-mediated
phosphorylation enhances Maf-transforming activity. Mol Cell.
2007 Nov 30;28(4):584-97
Sii-Felice K, Pouponnot C, Gillet S, Lecoin L, Girault JA,
Eychène A, Felder-Schmittbuhl MP. MafA transcription factor is
phosphorylated by p38 MAP kinase. FEBS Lett. 2005 Jul
4;579(17):3547-54
Eychène A, Rocques N, Pouponnot C. A new MAFia in cancer.
Nat Rev Cancer. 2008 Sep;8(9):683-93
Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A,
Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K,
Kudo T, Engel JD, Yamamoto M, Takahashi S. MafA is a key
regulator of glucose-stimulated insulin secretion. Mol Cell Biol.
2005 Jun;25(12):4969-76
Shao C, Cobb MH. Sumoylation regulates the transcriptional
activity of MafA in pancreatic beta cells. J Biol Chem. 2009 Jan
30;284(5):3117-24
Pouponnot C, Sii-Felice K, Hmitou I, Rocques N, Lecoin L,
Druillennec S, Felder-Schmittbuhl MP, Eychène A. Cell context
reveals a dual role for Maf in oncogenesis. Oncogene. 2006
Mar 2;25(9):1299-310
Pouponnot C, Eychène A. MAFA (v-maf musculoaponeurotic
fibrosarcoma oncogene homolog A (avian)). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(3):235-237.
This article should be referenced as such:
Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events
in the pathogenesis of multiple myeloma. Best Pract Res Clin
Haematol. 2007 Dec;20(4):571-96
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
237
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Review
MAP3K7 (mitogen-activated protein kinase kinase
kinase 7)
Hui Hui Tang, Kam C Yeung
Department of Cancer Biology and Biochemistry, College of Medicine, Univeristy of Toledo, Health Science
Campus, 3035 Arlington Ave., Toledo, OH 43614, USA (HHT, KCY)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MAP3K7ID454ch6q15.html
DOI: 10.4267/2042/44699
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
of housekeeping genes: the absence of TATA box, the
presence of CpG island and SP1 binding sites.
Other names: TAK1; TGF1a
HGNC (Hugo): MAP3K7
Location: 6q15
Transcription
Four alternatively spliced transcripts encoding 4
distinct isoforms because of the presence or absence of
alternative exons 12 or/and 16 are detected.
Variant A: It lacks an in-frame coding segment, exon
12.
Variant B: This variant contains both alternative exons
12 and 16 and encodes the longest isoform.
Variant C: Variant C lacks the exon 16 resulting in a
frame shift in exon 17. The resulting isoform C has a
distinct and shorter C terminus when compared with
variants A and B.
Variant D: Variant D lacks both exons 12 and 16.
The regulation of the TAK1 mRNA alternative splicing
is tissue specific. The different variants of TAK1 may
have specialized functions.
DNA/RNA
Description
MAP3K7/TAK1 gene spans 71 kb of DNA and
contains 17 exons and 16 introns. Exon 1 contains the
5' UTR of the mRNA and encodes 40 amino acid of Nterminal of the protein. Exons 2 to 8 encode the kinase
domain. Exon 17 encodes the carboxyl end of the
TAK1 protein and contains the 3'UTR. Exon 12 and
exon 16 are alternative exons.
The promoter is located between 799 bp and 1215 bp
upsteam of the exon 1. The promoter has the character
A: The 17 exons are shown as black vertical bars. The exon numbers are shown on top of each exon. The CpG island is shown as a
white box. The positions of exons in the cDNA are 1-282, 283-393, 394-459, 460-505, 506-644, 645-768, 770-898, 899-1029, 1030-1111,
1112-1242, 1243-1372, 1373-1453, 1454-1518, 1519-1624, 1625-1686, 1687-1802, and 1803-2850. The sizes (in base pairs) of intron 1
to 16 are 14956, 3073, 6891, 1407, 3451, 2913, 1278, 1499, 2290, 659, 2625, 8150, 12553, 4358, 695, and 1765, respectively.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
238
MAP3K7 (mitogen-activated protein kinase kinase kinase 7)
Tang HH, Yeung KC
B: MAP3K7 transcripts.
Independently, Sakurai et al. (1998) cloned hTAK1 as
well as two alternatively spliced isoforms. Human
TAK1a (Variant A) has 99.3% identity to murine
TAK1. TAK1b (Variant B) had an insertion of 27
amino acids and TAK1c had a deletion of 39 amino
acids in the carboxyl-terminal region. The catalytic
domains of these three isoforms were 100% identical to
that of murine TAK1. The mRNA for TAK1a and
TAK1b were expressed in Hela, Jurkat and THP1 cells
and TAK1a mRNA expessed predominantly in these
cell lines. TAK1c mRNA (Variant C) was expressed
only in Hela cells. Northern blot analysis revealed the
expression of TAK1 mRNA in all the human tissues
examined with the size of 3.2 and 5.7 kb. Dempsey et
al. (2000) identified a fourth splice variant of TAK1
called TAK1d (Variant D). TAK1d lacked the two
alternative exons and encoded a 491 amino acid
protein. TAK1a and b were the most abundant forms in
most tissues examined. The carboxyl-end variant
TAK1 proteins were unlikely to interfere with the
catalytic activity of TAK1 or its interaction with TAB1
since both of which involve the N terminus, but may
affect its interaction with TAB2 which associates with
the carboxyl-ends of the TAK1 proteins.
Pseudogene
No pseudogene of MAP3K7/TAK1 was reported in
human.
Protein
Note
MAP3K7/TAK1 isoform B contains 606 amino acids
(aa) and has a predicted molecular weight of 67 kDa,
isoform D contains 491 aa and has a predicted
molecular weight of 53.7 kDa, isoform C contains 518
aa and has a predicted molecular weight of 56.7 kDa,
and isoform A contains 579 aa and has a predicted
molecular weight of 64 kDa.
Description
MAP3K7/TAK1 was first identified by screening a
mouse cDNA library for clones that could act as
MAPKKKs. The mouse TAK1 cDNA encodes a 579amino acid protein. The mouse TAK1 protein contains
a 300-residue COOH-terminal domain and a putative
NH2-terminal protein kinase catalytic domain.
The kinase domain has approximately 30% identity to
the catalytic domains of Raf-1 and MEKK1. Kondo et
al. (1998) cloned human TAK1 from lung cDNA
library by screening with mouse TAK1 sequence.
Human TAK1 gene encodes a 579-amino-acid protein.
The hTAK1 gene has 91.8% identity with the mTAK1
gene at the nucleotide level and has 99.3% to that at the
amino acid level. Human TAK1 mRNA with a size of
3.0 kb was observed to express in all the tissues
examined by Northern blotting. Kondo et al. (1998)
found 2 isoforms of TAK1. Isoform 2 had an insertion
of 27 amino acids between amino acids 403 and 404 of
isoform 1 which corresponded to the mTAK1 sequence
previously identified by Yamaguchi et al. (1995). The
two isoforms were expressed at different ratios.
Isoform 1 (Variant A) was predominantly expressed in
brain, heart and spleen while the isoform 2 (Variant B)
was preferentially in the kidney.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Expression
TAK1 was ubiquitously expressed in all tissues.
TAK1a (variant A) was the most abundant form in
heart, liver, skeletal muscle, ovary, spleen and
peripheral blood mononuclear cells; TAK1b (Variant
B) was more abundant in brain, kidney, prostate and
small intestine; TAK1c (Variant C) is ubiquitously
expressed and predominantly in prostate; and TAK1d
(Variant D) existed in most tested tissues as a minor
variant.
Localisation
TAK1 is mostly localized in cytoplasm.
Function
TAK1 is a member of the serine/threonine protein
239
MAP3K7 (mitogen-activated protein kinase kinase kinase 7)
Tang HH, Yeung KC
kinase family. It can be activated by transforming
growth factor-beta (TGF-b) and TAK1 deletion mutant
missing the N-terminal 22 amino acid is constitutively
active. In response to TGF-b, TAK1 can phosphorylate
and activate MAP kinase kinases MKK3, MKK4 and
MKK6. TAK1 can activate NF-kB in the presence of
TAB1. TAK1 is also involved in pro-inflammatory
cytokines signaling by activa-ting two kinase pathways.
One is a MAPK cascade that leads to the activation of
JNK and the other is IkB kinase cascade that causes the
activation of NF-kB. It was shown that TRAF6 is a
signal mediator that activates IKK and JNK in response
to pro-inflammatory cytokine interleukin 1. The
activation of IKK by TRAF6 requires two intermediary
factors, TRAF6-regulated IKK activator 1 (TRIKA1)
and TRIKA2. TRIKA1 is an ubiquitin-conjugating
enzyme complex consisted of Ubc13 and Uev1A.
TRIKA1, together with TRAF6, catalyze the formation
of a Lys63-linked polyubi-quitin chain that mediates
IKK activation. TRIKA2 is composed of TAK1, TAB1
and TAB2. The activation of TAK1 kinase complex is
dependent on its polyubiquitination by the TRAF6-Ubc
complex and phosphorylation of several residues within
the kinase activation loop by yet-to-be identified
kinases. The ubiquitinated TAK1 can phosphorylate
IKKbeta specifically at S177 and S181. Mutation
analysis revealed that a point mutation in the ATPbinding domain of TAK1 (K63W), which abolished its
kinase activity, was unable to activate IKK. TAK1 was
activated by auto-phosphorylation on Ser192 and dual
phosphorylation of Thr-178 and Thr-184 residues
within the activation loop. Mutation of a conserved
serine residue (Ser192) in the activation loop between
kinase domain VII and VIII abrogated the
phosphorylation and activation of TAK1. TAK1 is
linked to TRAFs by two adaptor proteins TAB2 and
TAB3. The interaction of TAB2/TAB3 with TAK1 is
essential for the activation of signaling pathway
mediated by IL-1.
It was shown that protein phosphatase 2Cepsilon
(PP2Cepsilon) inhibited the IL-1 and TAK1 induced
activation of MKK4-JNK or MKK3-p38 signaling
pathway. PP2Cepsilon inactivated TAK1 by
associating with and dephosphorylating TAK1. A type2A phosphatase, protein phosphatase 6 (PP6), was also
identified as a TAK1-binding protein. PP6 repressed
TAK1 activity by dephos-phorylating Thr187.
Implicated in
Homology
Note
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL), a member of TNFa ligand
family, induces apoptosis in a variety of tumor cells.
TRAIL induced the delayed phospho-rylation of TAK1
in human cervical carcinoma HeLa cells. TRAIL
induced apoptosis was enhanced by downregulation of
TAK1.
Breast cancer
Note
TGF-b1 signaling is involved in tumor angiogenesis
and metastasis by regulating matrix proteosis. MMP-9
is an important component of these TGF-b1 responses.
TAK1 is important for TGF-b1 regulation of MMP9
and metastatic potential of breast cancer cell line
MDA-MB231. Suppression of TAK1 reduces the
expression of MMP9 and tumor cell invasion. TAK1
and NFkB are required for the human MCF10A-CA1a
breast cancer cells to undergo invasion in response to
TGF-b. A novel TAB1:TAK1: IKKb: NFkB signaling
axis forms aberrantly in breast cancer cells and enables
oncogenic signaling by TGF-b.
Lung cancer
Note
Mutation analysis: Study on 39 lung cancer specimens
and 16 lung cancer cell lines indicated that hTAK1 was
not a frequent target for genetic alternations in lung
cancer.
TAK1 variant D activated by siRNAs of specific
sequences leads to down stream activation of p38
MAPK and JNK but not NFkB pathway. In human lung
cancer cell line NCI-H460 the activation of these
pathway cause cell cycle arrest and apoptosis. It
suggests that TAK1 D may be a new and promising
therapeutic target for the treatment of non-small cell
lung cancer. Telomeres are essential elements at the
ends of chromosomes that contribute to chromosomal
stability. The length of the telomere is maintained by
the telomerase holoenzyme, which contains the reverse
trans-criptase hTERT as a major enzymatic subunit.
The activity of telomerase is absent in most normal
human cells because of the downregulation of the
hTERT transcript resulting in the shortening of
telomeres after each replicative cycle. However, in
immortalized cells and cancer cells, the telomere
lengths are maintained through an increase in hTERT
expression. TAK1 can repress the transcription of
hTERT in A549 human lung adenocarcinoma cell line
and this repression is caused by recruitment of HDAC
to the hTERT promoter.
Cervical carcinoma
Human TAK1-like (TAKL) gene encoded a 242 amino
acid protein which shared a homology with human
TAK1. The amino acid sequences of TAK1 were
highly conserved between human and mouse.
Mutations
Note
No mutation of human MAP3K7 was reported.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
240
MAP3K7 (mitogen-activated protein kinase kinase kinase 7)
Tang HH, Yeung KC
Sakurai H, Shigemori N, Hasegawa K, Sugita T. TGF-betaactivated kinase 1 stimulates NF-kappa B activation by an NFkappa B-inducing kinase-independent mechanism. Biochem
Biophys Res Commun. 1998 Feb 13;243(2):545-9
Head and neck squamous cell
carcinoma
Note
NFkB was constitutively activated in head and neck
squamous cell carcinoma (HNSCC). Constitutive
activation of NFkB in HNSCC was caused by
constitutive activation of IKK. Constitutive activa-tion
of NFkB is mediated through the TRADD-TRAF2RIP-TAK1-IKK pathway.
Dempsey CE, Sakurai H, Sugita T, Guesdon F. Alternative
splicing and gene structure of the transforming growth factor
beta-activated kinase 1. Biochim Biophys Acta. 2000 Dec
15;1517(1):46-52
Kishimoto K, Matsumoto K, Ninomiya-Tsuji J. TAK1 mitogenactivated protein kinase kinase kinase is activated by
autophosphorylation within its activation loop. J Biol Chem.
2000 Mar 10;275(10):7359-64
Arthritis
Lee J, Mira-Arbibe L, Ulevitch RJ. TAK1 regulates multiple
protein
kinase
cascades
activated
by
bacterial
lipopolysaccharide. J Leukoc Biol. 2000 Dec;68(6):909-15
Note
Exercise/joint mobility has therapeutic potency for
inflammatory joint diseases such as rheumatoid and
osteoarthritis.
The
biomechanical
signals
at
physiological magnitudes are potent inhibitors of
inflammation induced by NFkB activation in
fibrochondrocytes. The biomechanical signals exert
anti-inflammatory effects by inhibiting phosphorylation of TAK1.
JNK is essential for metalloproteinase (MMP) gene
expression and joint destruction in inflammatory
arthritis. TAK1 is an upstream kinase of JNK. TAK1
play an important role for the IL1b induced JNK
activation and the JNK induced gene expression in
fibroblast-like synoviocytes (FLSs). It suggests that
TAK1 is a potential therapeutic target to modulate
synoviocyte activation in rheumatoid arthritis (RA).
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.
TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature.
2001 Jul 19;412(6844):346-51
Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J,
Matsumoto K, Kobayashi T, Tamura S. Regulation of the
interleukin-1-induced signaling pathways by a novel member of
the protein phosphatase 2C family (PP2Cepsilon). J Biol
Chem. 2003 Apr 4;278(14):12013-21
Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J,
Matsumoto K, Gaynor RB. TAK1 is critical for IkappaB kinasemediated activation of the NF-kappaB pathway. J Mol Biol.
2003 Feb 7;326(1):105-15
Li J, Ji C, Yang Q, Chen J, Gu S, Ying K, Xie Y, Mao Y.
Cloning and characterization of a novel human TGF-beta
activated kinase-like gene. Biochem Genet. 2004 Apr;42(34):129-37
Inflammation
Kishida S, Sanjo H, Akira S, Matsumoto K, Ninomiya-Tsuji J.
TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and
assembly of TRAF6 with IKK in the IL-1 signaling pathway.
Genes Cells. 2005 May;10(5):447-54
Note
Pro-inflammatory molecules lipopolysaccharide and
Interleukin 1 trigger the activation of TAK1, which in
turn activates multiple kinase JNK, p38, IKK and
PKB/Akt which are important components of kinase
cascades involved in inflammation. Thus TAK1 plays
an important role in inflammation.
Choo MK, Kawasaki N, Singhirunnusorn P, Koizumi K, Sato S,
Akira S, Saiki I, Sakurai H. Blockade of transforming growth
factor-beta-activated kinase 1 activity enhances TRAILinduced apoptosis through activation of a caspase cascade.
Mol Cancer Ther. 2006 Dec;5(12):2970-6
Kajino T, Ren H, Iemura S, Natsume T, Stefansson B,
Brautigan DL, Matsumoto K, Ninomiya-Tsuji J. Protein
phosphatase 6 down-regulates TAK1 kinase activation in the
IL-1 signaling pathway. J Biol Chem. 2006 Dec
29;281(52):39891-6
Human airway epithelial cells
Note
Act1/TRAF6/TAK1-mediated
NF-kB
activation
stimulated by IL-17A regulates gene induction in
human airway epithelial cells. Dominant negative
TAK1 reduces IL-17A induced gene expression.
Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U,
Lin SC, Wu H, Darnay BG. TAK1-dependent signaling requires
functional interaction with TAB2/TAB3. J Biol Chem. 2007 Feb
9;282(6):3918-28
References
Hammaker DR, Boyle DL, Inoue T, Firestein GS. Regulation of
the JNK pathway by TGF-beta activated kinase 1 in
rheumatoid arthritis synoviocytes. Arthritis Res Ther.
2007;9(3):R57
Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten
AM. TAK1: molecular cloning and characterization of a new
member of the nuclear receptor superfamily. Mol Endocrinol.
1994 Dec;8(12):1667-80
Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, et al.
Identification of a member of the MAPKKK family as a potential
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22;270(5244):2008-11
Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin
XL, Darnay BG, Chaturvedi MM, Aggarwal BB. Evidence that
TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates
constitutive NF-kappaB activation and proliferation in human
head and neck squamous cell carcinoma. Oncogene. 2007
Mar 1;26(10):1385-97
Kondo M, Osada H, Uchida K, Yanagisawa K, Masuda A,
Takagi K, Takahashi T, Takahashi T. Molecular cloning of
human TAK1 and its mutational analysis in human lung cancer.
Int J Cancer. 1998 Feb 9;75(4):559-63
Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A,
Guttridge DC, Agarwal S. Biomechanical signals suppress
TAK1 activation to inhibit NF-kappaB transcriptional activation
in fibrochondrocytes. J Immunol. 2007 Nov 1;179(9):6246-54
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241
MAP3K7 (mitogen-activated protein kinase kinase kinase 7)
Tang HH, Yeung KC
Maura M, Katakura Y, Miura T, Fujiki T, Shiraishi H, Shirahata
S.. Molecular Mechanism of TAK1-Induced Repression of
hTERT Transcription. Cell Technology for Cell Products, R.
Smith (ed.), 91-93. 2007 Springer.
Safina A, Ren MQ, Vandette E, Bakin AV. TAK1 is required for
TGF-beta 1-mediated regulation of matrix metalloproteinase-9
and metastasis. Oncogene. 2008 Feb 21;27(9):1198-207
Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, et al.
Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is
required for interleukin (IL)-1-mediated optimal NFkappaB and
AP-1 activation as well as IL-6 gene expression. J Biol Chem.
2008 Sep 5;283(36):24497-505
Honorato B, Alcalde J, Martinez-Monge R, Zabalegui N,
Garcia-Foncillas J. TAK1 mRNA expression in the tumor tissue
of locally advanced head and neck Cancer Patients. Gene
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Kodym R, Kodym E, Story MD. Sequence-specific activation of
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This article should be referenced as such:
Tang HH, Yeung KC. MAP3K7 (mitogen-activated protein
kinase kinase kinase 7). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(3):238-242.
Neil JR, Schiemann WP. Altered TAB1:I kappaB kinase
interaction promotes transforming growth factor beta-mediated
nuclear factor-kappaB activation during breast cancer
progression. Cancer Res. 2008 Mar 1;68(5):1462-70
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
242
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MCPH1 (microcephalin 1)
Yulong Liang, Shiaw-Yih Lin, Kaiyi Li
Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA (YL, KL); Department of
Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA
(SYL)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MCPH1ID44370ch8p23.html
DOI: 10.4267/2042/44700
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
and/or tumour development. In addition, indivi-duals
who harbor a germline mutation of MCPH1 gene may
be highly susceptible to an autosomal recessive
neurological disorder, called primary microcephaly.
Identity
Other names: BRIT1; MCT
HGNC (Hugo): MCPH1
Location: 8p23.1
Local order: According to NCBI Map Viewer, genes
flanking MCPH1 in telomere to centromere direction
on 8p23.1 are: ANGPT2 (angiopoietin 2); MCPH1
(also BRIT1); AGPAT5 (1-acylglycerol-3-phosphate
O-acyltransferase
5
(lysophosphatidic
acid
acyltransferase, epsilon)); XKR5 (XK, Kell blood
group complex subunit-related family, member 5);
DEFB1 (defensin, beta 1); DEFA6 (defensin, alpha 6,
Paneth cell-specific).
Note
MCPH1 is one of DNA damage response proteins that
interact with other DNA damage and repair proteins
and signal transducers, form a DNA damage response
protein complex which can be seen through
immunofluorescent microscopy, and participate into
DNA repair, cell cycle checkpoint control, and
eventually maintain genomic integrity. The aberrant
expression of MCPH1 is observed in ovarian cancer
and breast cancer tissues and cell lines. Thus,
functional impairment of MCPH1 may significantly
contribute to tumour susceptibility
DNA/RNA
Description
According to Entrez-Gene, MCPH1 gene maps to
NC_000008.9 in the region between 6251529 and
6493434 on the plus strand and spans across 241.9 kilo
bases. According to GenBank, MCPH1 has 14 exons,
the sizes being 90, 92, 119, 88, 115, 144, 90, 1155, 110,
38, 163, 78, 238, and 5512 bp.
Transcription
8032 bp mRNA (NM_024596.2), 2508 bp open reading
frame.
Protein
Note
MCPH1 has three BRCA1 carboxyl-terminal (BRCT)
domains, so it is regarded as a protein family member
involved in DNA damage repair and checkpoint
control.
The protein of MCPH1 contains three BRCT domains, the nuclear localization signal motif and the large middle IMPDH domain. (AA,
amino acids).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
243
MCPH1 (microcephalin 1)
Liang Y, et al.
duplex and facilitating the homology search during the
establishment of joint molecules. Lack of MCPH1 can
alleviate localization of RAD51 onto the DNA break
sites. So MCPH1 is strongly implicated in HR.
Role of BRIT1 in cell cycle control: MCPH1 has been
demonstrated to regulate the expression of BRCA1 and
Chk1 and required for activation of intra-S and G2/M
cell cycle checkpoint after cellular exposure to ionizing
radiation. In the absence of MCPH1, BRCA1 and
ChK1 expression is significantly reduced and NBS1
fails to be phosphorylated, leading to loss of intra-S and
G2/M checkpoint control. Cells derived from a microcephaly patient (MCPH1 defective) maintain a
persistent level of CDC25A and reduced level of Cdk1cyclin B complex, both of which attributes to entry of
mitosis. So besides expression control of ChK1 and
BRCA1, MCPH1 prevents premature entry into mitosis
in an ATR-dependent and ATR-independent manner.
Description
MCPH1 protein contains 835 amino acids with about
110 kDa of the molecular weight. According to
MotifScan prediction, MCPH1 has three BRCT
domains, one nuclear localization signal motif and the
large central IMPDH domain as depicted in the
diagram above. The BRCT domains of MCPH1, one in
N-terminus (N-BRCT), the other two tandemly
arranged in C-terminus (C-BRCTs), specifically bind to
the phosphorylated proteins commonly involved in
DNA damage response pathways. The N-BRCT is
required for centrosomal localization in irradiated cells,
and also essential to rescue the premature chromosome
condensation in MCPH1-deficient cells. C-BRCTs
direct self-oligo-merization of MCPH1, and are
necessary for ionizing radiation-induced foci formation.
The function of IMPDH domain predicted by
MotifScan is not clear yet. However, the region
(residues 376-485) in the central IMPDH domain (or
middle domain), binding with Condension II,
participates in homologous recombination.
Homology
According to NCBI-HomoloGene:
Chimpanzee
(Pan
troglodytes):
MCPH1
(NP_001009010.1, 835 aa)
Dog (Canis familiaris): MCPH1 (NP_001003366.1,
850 aa)
Rat (Rattus norvegicus): MCPH1 (XP_225006.4, 986
aa)
Mouse (Mus musculus): MCPH1 (NP_775281.2, 822
aa)
Zebrafish (Danio rerio): zgc:136403 (NP_001035453.1,
422 aa)
Drosophila (Drosophila melanogaster): CG30038
(NP_725086.2, 219 aa)
Expression
MCPH1 is ubiquitously expressed in human with the
higher levels observed in the brain, testes, pancreas and
liver. It is a putative tumor suppressor and the aberrant
expression of MCPH1 is correlated with ovarian and
breast cancer. This reduced expression of MCPH1 may
have been caused by gene deletion detected by highdensity array comparative genomic hybridization
(CGH).
Localisation
Mainly localized in nucleus.
Mutations
Function
Note
Three point mutations in the autosomal recessive
mental retardation patients have been described for
MCPH1 so far. Two mutations (S25X and 427insA)
lead to premature stop condon, and one (T27R) leads to
missense mutation in the N-terminal BRCT domain. A
non-synonymous SNP (V761A in BRCA1 C-terminus
(BRCT) domain) of MCPH1 is significantly associated
with cranial volume in Chinese males. In addition, a
deletion of approximately 150-200 kb, encompassing
the promoter and the first six exons of the MCPH1
gene, was revealed by Array-based homozygosity
mapping and high-resolution microarray-based
comparative genomic hybridization (array CGH).
However, the patients with this deletion just showed
borderline of mild microcephaly.
MCPH1 function in DNA damage response: MCPH1
can modulate activities of two distinct DNA damage
repair networks, the ATM (ataxia telangiectaisia
mutated) pathway and the ATR (ATM and Rad3related) pathway. Upon exposure to DNA damaging
reagents, MCPH1 co-localizes with numerous proteins
associated with these two signaling pathways including
gamma-H2AX, MDC1, 53BP1, NBS1, p-ATM, ATR,
p-RAD17 and p-RPA34. In the absence of MCPH1, all
of these proteins with the exception of gamma-H2AX,
fail to localize to sites of DNA damage. The depletion
of MCPH1 inhibits the recruitment of phosphorylated
ATM to double-stranded DNA break ends, and
subsequently impair t phosphory-lation of multiple
down-stream members of the ATM pathway. MCPH1
deficiency
also
abolishes
the
UV-induced
phosphorylation of RPA34 and reduces the levels of
phosphorylated RAD17, suggesting the roles of
MCPH1 in the ATR path-way. Rad51, a homolog of
the bacterial RecA, is a central executioner in
homologous recombination (HR), catalyzing the
invasion of the single stranded DNA in a homologous
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Implicated in
Ovarian cancers
Note
Aberrations of MCPH1 have been identified in various
human cancers.
244
MCPH1 (microcephalin 1)
Liang Y, et al.
Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD,
Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson
AP. Mutations in microcephalin cause aberrant regulation of
chromosome condensation. Am J Hum Genet. 2004
Aug;75(2):261-6
Disease
MCPH1 DNA copy number was substatially decreased
in 40% of advanced epithelial ovarian cancer, and its
mRNA levels were also dramatically decreased in 63%
of ovarian cancer.
Xu X, Lee J, Stern DF. Microcephalin is a DNA damage
response protein involved in regulation of CHK1 and BRCA1. J
Biol Chem. 2004 Aug 13;279(33):34091-4
Breast cancers
Disease
MCPH1 mRNA and protein levels was aberrantly
reduced in several breast cancer cell lines.
Prognosis
Additionally, reduced MCPH1 expression correla-ted
with the duration of the relapse-free intervals and with
the occurrence of metastasis in breast cancers. BRIT1
deficiency may contribute to development and
aggressive nature of breast tumors.
Lin SY, Rai R, Li K, Xu ZX, Elledge SJ. BRIT1/MCPH1 is a
DNA damage responsive protein that regulates the Brca1Chk1 pathway, implicating checkpoint dysfunction in
microcephaly. Proc Natl Acad Sci U S A. 2005 Oct
18;102(42):15105-9
Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D,
Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G,
Neitzel H. The first missense alteration in the MCPH1 gene
causes autosomal recessive microcephaly with an extremely
mild cellular and clinical phenotype. Hum Mutat. 2005
Nov;26(5):496
Primary microcephaly
Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H,
Jackson AP, Jeggo PA, O'Driscoll M. Regulation of mitotic
entry by microcephalin and its overlap with ATR signalling. Nat
Cell Biol. 2006 Jul;8(7):725-33
Disease
Primary microcephaly is an autosomal recessive
disorder, in which there is a marked reduction in brain
size. One form of primary microcephaly, MCPH, is
caused by mutation in the gene encoding microcephalin
1 (that is, MCPH1). In these patients, the MCPH1deficient cells show cellular phenotype of premature
chromosome condensation in the early G2 phase of the
cell cycle, which, therefore, appears to be a useful
diagnostic marker for these individuals. As mentioned
above, several mutations of MCPH1 have been
observed in these patients, including S25X, 427insA,
T27R, V761A and 5'-deletion of a large portion
encompassing the promoter region and first six exons,
especially the later two showing strong correlation with
micro-cephaly.
Chaplet M, Rai R, Jackson-Bernitsas D, Li K, Lin SY.
BRIT1/MCPH1: a guardian of genome and an enemy of
tumors. Cell Cycle. 2006 Nov;5(22):2579-83
Garshasbi M, Motazacker MM, Kahrizi K, Behjati F, Abedini
SS, Nieh SE, Firouzabadi SG, Becker C, Rüschendorf F,
Nürnberg P, Tzschach A, Vazifehmand R, Erdogan F, Ullmann
R, Lenzner S, Kuss AW, Ropers HH, Najmabadi H. SNP arraybased homozygosity mapping reveals MCPH1 deletion in
family with autosomal recessive mental retardation and mild
microcephaly. Hum Genet. 2006 Feb;118(6):708-15
Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, Lahad JP,
Liang J, Mills GB, Meric-Bernstam F, Lin SY. BRIT1 regulates
early DNA damage response, chromosomal integrity, and
cancer. Cancer Cell. 2006 Aug;10(2):145-57
Wood JL, Singh N, Mer G, Chen J. MCPH1 functions in an
H2AX-dependent but MDC1-independent pathway in response
to DNA damage. J Biol Chem. 2007 Nov 30;282(48):35416-23
PCC syndrome
Disease
Premature chromosome condensation (PCC) syndrome
is
characterized
by
premature
chromosome
condensation in the early G2 phase. This disorder is
similar to microcephalin 1, and can also be caused by
MCPH1 mutations.
Jeffers LJ, Coull BJ, Stack SJ, Morrison CG. Distinct BRCT
domains in Mcph1/Brit1 mediate ionizing radiation-induced
focus formation and centrosomal localization. Oncogene. 2008
Jan 3;27(1):139-44
Wang JK, Li Y, Su B. A common SNP of MCPH1 is associated
with cranial volume variation in Chinese population. Hum Mol
Genet. 2008 May 1;17(9):1329-35
References
Wood JL, Liang Y, Li K, Chen J. Microcephalin/MCPH1
associates with the Condensin II complex to function in
homologous recombination repair. J Biol Chem. 2008 Oct
24;283(43):29586-92
Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y,
Mannan J, Karbani G, Corry P, Levene MI, Mueller RF,
Markham AF, Lench NJ, Woods CG. Primary autosomal
recessive microcephaly (MCPH1) maps to chromosome 8p22pter. Am J Hum Genet. 1998 Aug;63(2):541-6
Yang SZ, Lin FT, Lin WC. MCPH1/BRIT1 cooperates with
E2F1 in the activation of checkpoint, DNA repair and
apoptosis. EMBO Rep. 2008 Sep;9(9):907-15
Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM,
Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G,
Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG.
Identification of microcephalin, a protein implicated in
determining the size of the human brain. Am J Hum Genet.
2002 Jul;71(1):136-42
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
This article should be referenced as such:
Liang Y, Lin SY, Li K. MCPH1 (microcephalin 1). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(3):243-245.
245
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
NKX3-1 (NK3 homeobox 1)
Liang-Nian Song, Edward P Gelmann
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA (LNS,
EPG)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/NKX31ID41541ch8p21.html
DOI: 10.4267/2042/44701
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
terminal domain (residues 1-123), one homeo-domain
(residues 124-183), and one C-terminal domain
(residues 184-234).
Identity
Other names: NKX3 BAPX2; NKX3A; NKX3.1
HGNC (Hugo): NKX3-1
Location: 8p21.2
Local order: Gene orientation: telomere-3' NKX3.1 5'centromere.
Expression
Expression is restricted to the adult murine prostate and
bulbourethral
gland.
During
early
murine
embryogenesis NKX3-1 expression has also been
detected in developing somites and testes. In the adult
human expression is seen in prostate epithelium, testis,
ureter, and pulmonary bronchial mucous glands.
DNA/RNA
Description
Localisation
The gene has two exons and one intron.
Nuclear.
Transcription
Function
Transcription takes place in a centromere --> telomere
orientation. The length of the processed mRNA is
about 3200 bp.
Binds to DNA to suppress transcription. Interacts with
transcription factors, e.g. serum response factor, to
enhance transcriptional activation. Binds to and
potentiates topoisomerase I DNA resolving activity.
Acts as prostate tumor suppressor.
Pseudogene
Not known.
Homology
Protein
Homeodomain protein with membership of the NKX
family.
Description
234 amino acids; 35-38 kDa, contains one N-
The gene for NKX3-1 comprises two exons of 334 and 2947 bp, respectively. The length of the intron is 964 bp. Positions of start and
stop codons are indicated.
NKX3-1 contains two exons encoding a 234-amino acid protein including a homeodomain (grey).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
246
NKX3-1 (NK3 homeobox 1)
Song LN, Gelmann EP
Pten+/- background. Further-rmore, by a variety of
mechanisms NKX3.1 expression is reduced in
noninvasive and early stage human prostate cancer,
suggesting that its decreased expression is one of the
earliest steps in the majority of human prostate cancers.
Mutations
Germinal
Twenty-one germ-line variants have been identified in
159 probands of hereditary prostate cancer families.
These variants were linked to prostate cancer risk in
hereditary prostate cancer families. For example, the
C154T (11% of the population) polymorphism
mutation is associated with prostatic enlargement and
prostate cancer risk. A T164A mutations in one family
cosegregates with prostate cancer in three affected
brothers. For a more complete list of identified
mutations,
please
visit
http://cancerres.aacrjournals.org/cgi/content/full/66/1/6
9.
References
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Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall DJ,
Gelmann EP, Abate-Shen C, Carter KC. A novel human
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Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen MM,
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Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC,
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Somatic
None.
Implicated in
Prescott JL, Blok L, Tindall DJ. Isolation and androgen
regulation of the human homeobox cDNA, NKX3.1. Prostate.
1998 Apr 1;35(1):71-80
Prostate Cancer
Disease
Prostate cancer is the most commonly diagnosed cancer
in American men and the second leading cause of
cancer-related deaths. Prostate cancer predominantly
occurs in the peripheral zone of the human prostate,
with roughly 5 to 10% of cases found in the central
zone. Disease development involves the temporal and
spatial loss of the basal epithelial compartment
accompanied by increased proliferation and
dedifferentiation of the luminal (secretory) epithelial
cells. Prostate cancer is a slow developing disease that
is typically found in men greater than 60 years of age
and incidence increases with increasing age.
Prognosis
PSA test combined with digital-rectal exams are used
to screen for the presence of disease. If the digitalrectal exams are positive, additional tests including
needle core biopsies are taken to assess disease stage
and grade. Patients with localized, prostate-restricted
disease are theoretically curable with complete removal
of the prostate (radical prostatectomy). Patients with
extra-prostatic disease are treated with hormone
(androgen ablation) therapy, radiation, and/or
antiandrogens; however, no curative treatments are
available for nonorgan confined metastatic disease.
Cytogenetics
Various forms of aneuploidy.
Oncogenesis
Nkx3.1 plays an essential role in normal murine
prostate development. Loss of function of Nkx3.1 leads
to defects in prostatic protein secretions and in ductal
morphogenesis. Loss-of-function of Nkx3.1 also
contributes to prostate carcinogenesis. For example,
Nkx3.1 mutant mice develop prostatic dysplasia.
Nkx3.1 loss potentiates prostate carcinogenesis in a
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Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, AbateShen C, Shen MM. Roles for Nkx3.1 in prostate development
and cancer. Genes Dev. 1999 Apr 15;13(8):966-77
Tanaka M, Lyons GE, Izumo S. Expression of the Nkx3.1
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Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G,
Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP,
Gelmann EP. Loss of NKX3.1 expression in human prostate
cancers correlates with tumor progression. Cancer Res. 2000
Nov 1;60(21):6111-5
Korkmaz KS, Korkmaz CG, Ragnhildstveit E, Kizildag S,
Pretlow TG, Saatcioglu F. Full-length cDNA sequence and
genomic organization of human NKX3A - alternative forms and
regulation by both androgens and estrogens. Gene. 2000 Dec
30;260(1-2):25-36
Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted
disruption of the Nkx3.1 gene in mice results in morphogenetic
defects of minor salivary glands: parallels to glandular duct
morphogenesis in prostate. Mech Dev. 2000 Jul;95(1-2):16374
Steadman DJ, Giuffrida D, Gelmann EP. DNA-binding
sequence of the human prostate-specific homeodomain protein
NKX3.1. Nucleic Acids Res. 2000 Jun 15;28(12):2389-95
Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG,
Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe,
regulates epithelial ductal branching and proliferation of the
prostate and palatine glands. Dev Dyn. 2000 Oct;219(2):24860
Xu LL, Srikantan V, Sesterhenn IA, Augustus M, Dean R, Moul
JW, Carter KC, Srivastava S. Expression profile of an
androgen regulated prostate specific homeobox gene NKX3.1
in primary prostate cancer. J Urol. 2000 Mar;163(3):972-9
Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert-Buck
MR, Vocke CD, Linehan WM, Ferretti JA. Expression studies
and mutational analysis of the androgen regulated homeobox
gene NKX3.1 in benign and malignant prostate epithelium. J
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Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK,
Humphrey PA, Milbrandt J. Conditional loss of Nkx3.1 in adult
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homeoprotein NKX3.1 and serum response factor. J Mol Biol.
2006 Jul 28;360(5):989-99
Li X, Guan B, Maghami S, Bieberich CJ. NKX3.1 is regulated
by protein kinase CK2 in prostate tumor cells. Mol Cell Biol.
2006 Apr;26(8):3008-17
Gelmann EP, Steadman DJ, Ma J, Ahronovitz N, Voeller HJ,
Swope S, Abbaszadegan M, Brown KM, Strand K, Hayes RB,
Stampfer MJ. Occurrence of NKX3.1 C154T polymorphism in
men with and without prostate cancer and studies of its effect
on protein function. Cancer Res. 2002 May 1;62(9):2654-9
Rodriguez Ortner E, Hayes RB, Weissfeld J, Gelmann EP.
Effect of homeodomain protein NKX3.1 R52C polymorphism
on prostate gland size. Urology. 2006 Feb;67(2):311-5
Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons
R, Shen MM, Abate-Shen C. Cooperativity of Nkx3.1 and Pten
loss of function in a mouse model of prostate carcinogenesis.
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2884-9
Simmons SO, Horowitz JM. Nkx3.1 binds and negatively
regulates the transcriptional activity of Sp-family members in
prostate-derived cells. Biochem J. 2006 Jan 1;393(Pt 1):397409
Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD,
Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen MM.
Nkx3.1; Pten mutant mice develop invasive prostate
adenocarcinoma and lymph node metastases. Cancer Res.
2003 Jul 15;63(14):3886-90
Zheng SL, Ju JH, Chang BL, Ortner E, Sun J, Isaacs SD, Sun
J, Wiley KE, Liu W, Zemedkun M, Walsh PC, Ferretti J,
Gruschus J, Isaacs WB, Gelmann EP, Xu J. Germ-line
mutation of NKX3.1 cosegregates with hereditary prostate
cancer and alters the homeodomain structure and function.
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Gelmann EP, Bowen C, Bubendorf L. Expression of NKX3.1 in
normal and malignant tissues. Prostate. 2003 May 1;55(2):1117
Bowen C, Stuart A, Ju JH, Tuan J, Blonder J, Conrads TP,
Veenstra TD, Gelmann EP. NKX3.1 homeodomain protein
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gene regulation during tumor initiation. Cancer Cell. 2003
Mar;3(3):273-83
Mogal AP, van der Meer R, Crooke PS, Abdulkadir SA.
Haploinsufficient prostate tumor suppression by Nkx3.1: a role
for chromatin accessibility in dosage-sensitive gene regulation.
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Shen MM, Abate-Shen C. Roles of the Nkx3.1 homeobox gene
in prostate organogenesis and carcinogenesis. Dev Dyn. 2003
Dec;228(4):767-78
Abate-Shen C, Shen MM, Gelmann E. Integrating
differentiation and cancer: the Nkx3.1 homeobox gene in
prostate organogenesis and carcinogenesis. Differentiation.
2008 Jul;76(6):717-27
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Danielsen H, Kung J, Sellers WR, Loda M, Saatcioglu F.
Analysis of androgen regulated homeobox gene NKX3.1
during prostate carcinogenesis. J Urol. 2004 Sep;172(3):11349
Holmes KA, Song JS, Liu XS, Brown M, Carroll JS. Nkx3-1 and
LEF-1 function as transcriptional inhibitors of estrogen receptor
activity. Cancer Res. 2008 Sep 15;68(18):7380-5
Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli
LR, Haddad BR, Gelmann EP. Deletion, methylation, and
expression of the NKX3.1 suppressor gene in primary human
prostate cancer. Cancer Res. 2005 Feb 15;65(4):1164-73
Markowski MC, Bowen C, Gelmann EP. Inflammatory
cytokines induce phosphorylation and ubiquitination of prostate
suppressor protein NKX3.1. Cancer Res. 2008 Sep
1;68(17):6896-901
Bethel CR, Faith D, Li X, Guan B, Hicks JL, Lan F, Jenkins RB,
Bieberich CJ, De Marzo AM. Decreased NKX3.1 protein
expression in focal prostatic atrophy, prostatic intraepithelial
neoplasia, and adenocarcinoma: association with gleason
score and chromosome 8p deletion. Cancer Res. 2006 Nov
15;66(22):10683-90
Zhang Y, Fillmore RA, Zimmer WE. Structural and functional
analysis of domains mediating interaction between the bagpipe
homologue, Nkx3.1 and serum response factor. Exp Biol Med
(Maywood). 2008 Mar;233(3):297-309
Ju JH, Maeng JS, Zemedkun M, Ahronovitz N, Mack JW,
Ferretti JA, Gelmann EP, Gruschus JM. Physical and
functional interactions between the prostate suppressor
Song LN, Gelmann EP. NKX3-1 (NK3 homeobox 1). Atlas
Genet Cytogenet Oncol Haematol. 2010; 14(3):246-248.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
This article should be referenced as such:
248
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PLXNB1 (plexin B1)
José Javier Gómez-Román, Montserrat Nicolas Martínez, Servando Lazuén Fernández, José
Fernando Val-Bernal
Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty,
University of Cantabria, Santander, Spain (JJGR, MN, SL, JFVB)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/PLXNB1ID43413ch3p21.html
DOI: 10.4267/2042/44702
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pseudogene
Identity
No.
Other
names:
KIAA0407;
MGC149167;
OTTHUMP00000164806; PLEXIN-B1; PLXN5; SEP
HGNC (Hugo): PLXNB1
Location: 3p21.31
Local order: The Plexin B1 gene is located between
FBXW12 and CCDC51 genes.
Protein
Description
2135 Amino acids (AA). Plexins are receptors for axon
molecular guidance molecules semaphorins. Plexin
signalling is important in pathfinding and patterning of
both neurons and developing blood vessels. Plexin-B1
is a surface cell receptor. When it binds to its ligand
SEMA4D it activates several pathways by binding of
cytoplasmic ligands, like RHOA activation and
subsequent changes of the actin cytoskeleton, axon
guidance, invasive growth and cell migration.
It monomers and heterodimers with PLXNB2 after
proteolytic processing. Binds RAC1 that has been
activated by GTP binding.
It binds PLXNA1 and by similarity ARHGEF11,
ARHGEF12, ERBB2, MET, MST1R, RND1, NRP1
and NRP2.
This family features the C-terminal regions of various
plexins. The cytoplasmic region, which has been called
a SEX domain in some members of this family is
involved in downstream signalling pathways, by
interaction with proteins such as Rac1, RhoD, Rnd1
and other plexins.
Three copies of a cysteine rich repeat are found in
Plexin. The function of the repeat is unknown.
Note
Size: 26,200 bases.
Orientation: minus strand.
DNA/RNA
Description
Functioning gene. 21.00 kb; 37 Exons.
Transcription
7097.00 bp; Number of transcripts: 1; Type:
Messenger.
Two alternatively truncated spliced variant, coding
secreted proteins (lacking the part of the extracellular
domains).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Expression
It is highly expressed in fetal kidney, digestive system
(from esophagus to colon), thyroid, prostate and
trachea and at slightly lower levels in fetal brain, lung,
249
PLXNB1 (plexin B1)
Gómez-Román JJ, et al.
female reproductive system (breast, uterus and ovary)
and liver.
Plexin B1 policlonal antibody in foetal human central nervous system. Positive staining in developing neurons.
Localisation
mutations in the cytoplasmic domain of the PLXNB1
gene in prostate cancer tissue. Mutations were found in
8 (89%) of 9 prostate cancer bone metastases, in 7
(41%) of 17 lymph node meta-stases, and in 41 (46%)
of 89 primary cancers. Forty percent of prostate cancers
contained the same mutation, and the majority of the
primary tumors showed overexpression of the plexinB1 protein. In vitro functional expression studies of the
3 most common mutations showed that the mutant
proteins resulted in increased cell motility, inva-sion,
adhesion, and lamellipodia extension compared to
wildtype. The mutations acted by hindering RAC1 and
RRAS binding and GTP activity.
Three isoforms have been identified: The isoform 1 is
located in cell membrane and the isoforms 2 and 3 are
secreted proteins.
Function
Plexin B1 has several molecular functions, like a
receptor activity, transmembrane receptor activity,
protein binding, semaphorin receptor and semaphorin
receptor binding. It is implicated in the next biological
processes: Signal transduction, intracellular signalling
cascade, multicellular organismal development, cell
migration and posi-tive regulation of axonogenesis.
Homology
Implicated in
It belongs to the plexin family and it contains 3
IPT/TIG domains and one Sema domain.
Breast cancer
Mutations
Prognosis
Loss of protein Plexin B1 expression is associated with
poor outcome in breast cancer ER (estrogen positive)
patients.
Somatic
Wong et al. (2007) identified 13 different somatic
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
250
PLXNB1 (plexin B1)
Gómez-Román JJ, et al.
ACHN, a marked reduction in proliferation rate is
found.
Renal cell carcinoma
Prostate carcinoma
Note
By reverse transcription-polymerase chain reaction
Note
13 somatic missense mutations in the cytoplasmic
domain of the Plexin-B1 gene have been reported.
Mutations were found in cancer bone metastases,
lymph node metastases, and in primary cancers.
Forty percent of prostate cancers contained the same
mutation. Overexpression of the Plexin-B1 protein was
found in the majority of primary tumors. The mutations
hinder Rac and R-Ras binding and R-RasGAP activity,
resulting in an increase in cell motility, invasion,
adhesion, and lamellipodia.
plexin B1 is expressed in nonneoplastic renal tissue,
and it is severely downregulated in clear cell renal
carcinomas. By immunohistochemistry on tissue
microarrays it was shown that plexin B1 protein is
absent in more than 80% of renal cell carcinomas.
Otherwise, all kinds of renal tubules showed strong
membrane reactivity.
When plexin B1 expression is induced with an
expression vector in the renal adenocarcinoma cell line
Plexin B1 in normal kidney tissue.
Tubular cortical and medular cells reactive
The same immunostaining after blocking peptide incubation.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
251
PLXNB1 (plexin B1)
Gómez-Román JJ, et al.
Plexin B1 loss of expression in three cases of renal cell carcinoma (clear cell upper right and left), and papillary (bottom right). One case
of renal clear cell carcinoma with PlexinB1 expression (bottom left).
Osteoarthritis
activation by Plexin-B1 and induces cell contraction in COS-7
cells. J Biol Chem. 2003 Jul 11;278(28):25671-7
Note
Using
semi-quantitative
reverse
transcription
polymerase chain reaction (RT-PCR) analysis, plexin
B1 (PLXNB1) was confirmed to be consis-tently
expressed at lower levels in osteoarthritis.
Disease
Degenerative bone disease.
Usui H, Taniguchi M, Yokomizo T, Shimizu T. Plexin-A1 and
plexin-B1 specifically interact at their cytoplasmic domains.
Biochem Biophys Res Commun. 2003 Jan 24;300(4):927-31
Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S.
Interplay between scatter factor receptors and B plexins
controls invasive growth. Oncogene. 2004 Jul 1;23(30):5131-7
Oinuma I, Ishikawa Y, Katoh H, Negishi M. The Semaphorin
4D receptor Plexin-B1 is a GTPase activating protein for RRas. Science. 2004 Aug 6;305(5685):862-5
References
Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEFmediated RhoA activation involves the receptor tyrosine kinase
ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80
Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano
M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM. A
family of transmembrane proteins with homology to the METhepatocyte growth factor receptor. Proc Natl Acad Sci U S A.
1996 Jan 23;93(2):674-8
Torres-Vázquez J, Gitler AD, Fraser SD, Berk JD, Van N
Pham, Fishman MC, Childs S, Epstein JA, Weinstein BM.
Semaphorin-plexin signaling guides patterning of the
developing vasculature. Dev Cell. 2004 Jul;7(1):117-23
Fujii T, Nakao F, Shibata Y, Shioi G, Kodama E, Fujisawa H,
Takagi S. Caenorhabditis elegans PlexinA, PLX-1, interacts
with transmembrane semaphorins and regulates epidermal
morphogenesis. Development. 2002 May;129(9):2053-63
Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1
induces endothelial cell migration through the activation of
PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway.
Mol Cell Biol. 2005 Aug;25(16):6889-98
Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A,
Comoglio PM, Di Renzo MF. Novel somatic mutations of the
MET oncogene in human carcinoma metastases activating cell
motility and invasion. Cancer Res. 2002 Dec 1;62(23):7025-30
Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L,
Comoglio PM, Bussolino F, Giordano S. Sema4D induces
angiogenesis through Met recruitment by Plexin B1. Blood.
2005 Jun 1;105(11):4321-9
Oinuma I, Katoh H, Harada A, Negishi M. Direct interaction of
Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
252
PLXNB1 (plexin B1)
Gómez-Román JJ, et al.
Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and
Rho kinase to promote the integrin-dependent activation of Akt
and ERK and endothelial cell motility. J Biol Chem. 2007 Nov
30;282(48):34888-95
B1 and the small GTPase Rac1. J Mol Biol. 2008 Apr
11;377(5):1474-87
Gómez Román JJ, Garay GO, Saenz P, Escuredo K, Sanz
Ibayondo C, Gutkind S, Junquera C, Simón L, Martínez A,
Fernández Luna JL, Val-Bernal JF. Plexin B1 is downregulated
in renal cell carcinomas and modulates cell growth. Transl
Res. 2008 Mar;151(3):134-40
Harduf H, Goldman S, Shalev E. Human uterine epithelial
RL95-2 and HEC-1A cell-line adhesiveness: the role of plexin
B1. Fertil Steril. 2007 Jun;87(6):1419-27
Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W,
Shen L, Park HW, Buck M. Binding of Rac1, Rnd1, and RhoD
to a novel Rho GTPase interaction motif destabilizes
dimerization of the plexin-B1 effector domain. J Biol Chem.
2007 Dec 21;282(51):37215-24
Swiercz JM, Worzfeld T, Offermanns S. ErbB-2 and met
reciprocally regulate cellular signaling via plexin-B1. J Biol
Chem. 2008 Jan 25;283(4):1893-901
Tong Y, Hota PK, Hamaneh MB, Buck M. Insights into
oncogenic mutations of plexin-B1 based on the solution
structure of the Rho GTPase binding domain. Structure. 2008
Feb;16(2):246-58
Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS,
Bott SR, Nariculam J, Box G, Munson P, Constantinou J,
Feneley MR, Klocker H, Eccles SA, Negishi M, Freeman A,
Masters JR, Williamson M. Plexin-B1 mutations in prostate
cancer. Proc Natl Acad Sci U S A. 2007 Nov
27;104(48):19040-5
This article should be referenced as such:
Gómez-Román JJ, Nicolas Martínez M, Lazuén Fernández S,
Val-Bernal JF. PLXNB1 (plexin B1). Atlas Genet Cytogenet
Oncol Haematol. 2010; 14(3):249-253.
Bouguet-Bonnet S, Buck M. Compensatory and long-range
changes in picosecond-nanosecond main-chain dynamics
upon complex formation: 15N relaxation analysis of the free
and bound states of the ubiquitin-like domain of human plexin-
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
253
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
RUVBL1 (RuvB-like 1 (E. coli))
Valérie Haurie, Aude Grigoletto, Jean Rosenbaum
INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (VH,
AG, JR)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL1ID44415ch3q21.html
DOI: 10.4267/2042/44703
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
The monomers contain three domains, of which the
first and the third are involved in ATP binding and
hydrolysis. The second domain is a DNA/RNA-binding
domain as demonstrated by structural homology and
nucleic acid binding assays. RUVBL1 assembles into
an hexameric structure with a central channel. Pure
RUVBL1 displays a marginal ATPase activity in vitro
and no detectable helicase activity (Matias et al., 2006).
RUVBL1 interacts with RUVBL2 to form a dodecamer
(Puri et al., 2007). This RUVBL1/ RUVBL2 complex
displays a significant ATPase activity and is likely one
of the functional forms of the proteins.
Sumoylation of RUVBL1 was reported in metastatic
prostate cancer cells (Kim et al., 2007).
1785bp mRNA.
Expression
Protein
Expression is ubiquitous but especially abundant in
heart, skeletal muscle and testis (Salzer et al., 1999).
RUVBL1 is overexpressed in several tumors : liver (Li
et al., 2005), colon (Carlson et al., 2003; Lauscher et
al., 2007), lymphoma (Nishiu et al., 2002), non-small
cell lung (Dehan et al., 2007). Overexpressions of
RUVBL1 in a large number of cancers and its possible
role in human cancers have been reported (reviewed in
Huber et al., 2008).
Identity
Other names: ECP54; INO80H; NMP238; PONTIN;
Pontin52; RVB1; TAP54-alpha; TIH1; TIP49; TIP49A
HGNC (Hugo): RUVBL1
Location: 3q21.3
DNA/RNA
Description
11 exons spamming 42840bp, 1371bp open reading
frame.
Description
456 amino acids, 50.2 kDa. RUVBL1 belongs to the
AAA+ ATPase superfamily (ATPases associa-ted with
diverse cellular activities) sharing conserved Walker A
and B motifs, arginine fingers, and sensor domains.
The structure of RuvBL1 has been determined by X-ray
crystallography and published in 2006 (Matias et al.,
2006).
Localisation
Cytoplasm and nucleus.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
254
RUVBL1 (RuvB-like 1 (E. coli))
Haurie V, et al.
Function
References
RUVBL1 plays roles in essential signaling path-ways
such as the c-Myc and beta-catenin pathways.
RUVBL1 appears notably required for the transforming activity of c-myc (Wood et al., 2000), betacatenin (Feng et al., 2003) and of the viral oncoprotein
E1A (Dugan et al., 2002).
RUVBL1 participates in the remodelling of chromatin
as a member of several complexes such as TRRAP,
several distinct HAT complexes and BAF53 (Wood et
al., 2000; Park et al., 2002; Feng et al., 2003).
It is also involved in transcriptional regulation
(reviewed in Gallant, 2007), DNA repair (Gospodinov
et al., 2008), snoRNP biogenesis (Watkins et al., 2002),
and telomerase activity (Venteicher et al., 2008).
RUVBL1 has a mitosis-specific function in regulating
microtubule assembly (Ducat et al., 2008).
RUVBL1 has been found expressed on the cell surface
where it participates in the activation of plasminogen
(Hawley et al., 2001).
Makino Y, Mimori T, Koike C, Kanemaki M, Kurokawa Y, Inoue
S, Kishimoto T, Tamura T. TIP49, homologous to the bacterial
DNA helicase RuvB, acts as an autoantigen in human.
Biochem Biophys Res Commun. 1998 Apr 28;245(3):819-23
Salzer U, Kubicek M, Prohaska R. Isolation, molecular
characterization, and tissue-specific expression of ECP-51 and
ECP-54 (TIP49), two homologous, interacting erythroid
cytosolic proteins. Biochim Biophys Acta. 1999 Sep
3;1446(3):365-70
Wood MA, McMahon SB, Cole MD. An ATPase/helicase
complex is an essential cofactor for oncogenic transformation
by c-Myc. Mol Cell. 2000 Feb;5(2):321-30
Hawley SB, Tamura T, Miles LA. Purification, cloning, and
characterization of a profibrinolytic plasminogen-binding
protein, TIP49a. J Biol Chem. 2001 Jan 5;276(1):179-86
Dugan KA, Wood MA, Cole MD. TIP49, but not TRRAP,
modulates c-Myc and E2F1 dependent apoptosis. Oncogene.
2002 Aug 29;21(38):5835-43
Nishiu M, Yanagawa R, Nakatsuka S, Yao M, Tsunoda T,
Nakamura Y, Aozasa K. Microarray analysis of geneexpression profiles in diffuse large B-cell lymphoma:
identification of genes related to disease progression. Jpn J
Cancer Res. 2002 Aug;93(8):894-901
Implicated in
Colon cancer
Park J, Wood MA, Cole MD. BAF53 forms distinct nuclear
complexes and functions as a critical c-Myc-interacting nuclear
cofactor for oncogenic transformation. Mol Cell Biol. 2002
Mar;22(5):1307-16
Disease
By immunohistochemistry, RUVBL1 expression was
found higher in 22 out of 26 cases where information
was available (Lauscher et al., 2007). The staining was
increased at the invasive margin of the tumors.
Increased RUVBL1 transcripts levels were also
reported in a smaller series (Carlson et al., 2003).
Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of
the box C/D motif is essential for nucleolar localization and is
required, along with the 15.5K protein, for the hierarchical
assembly of the box C/D snoRNP. Mol Cell Biol. 2002
Dec;22(23):8342-52
Carlson ML, Wilson ET, Prescott SM. Regulation of COX-2
transcription in a colon cancer cell line by Pontin52/TIP49a.
Mol Cancer. 2003 Dec 15;2:42
Large B cell lymphoma
Disease
Microarray analysis has identified an over-expression
of RUVBL1 in Advanced lymphomas as compared
with localized lymphomas (Nishiu et al., 2002).
Feng Y, Lee N, Fearon ER. TIP49 regulates beta-cateninmediated neoplastic transformation and T-cell factor target
gene induction via effects on chromatin remodeling. Cancer
Res. 2003 Dec 15;63(24):8726-34
Non Small cell lung cancer
Li C, Tan YX, Zhou H, Ding SJ, Li SJ, Ma DJ, Man XB, Hong
Y, Zhang L, Li L, Xia QC, Wu JR, Wang HY, Zeng R.
Proteomic analysis of hepatitis B virus-associated
hepatocellular carcinoma: Identification of potential tumor
markers. Proteomics. 2005 Mar;5(4):1125-39
Disease
Microarray analysis and subsequent RT-PCR have
shown an overexpression of RUVBL1 in NSCLC
(Dehan et al., 2007).
Cytogenetics
There is a frequent amplification of 3q21 in the same
samples (Dehan et al., 2007).
Matias PM, Gorynia S, Donner P, Carrondo MA. Crystal
structure of the human AAA+ protein RuvBL1. J Biol Chem.
2006 Dec 15;281(50):38918-29
Dehan E, Ben-Dor A, Liao W, Lipson D, Frimer H, Rienstein S,
Simansky D, Krupsky M, Yaron P, Friedman E, Rechavi G,
Perlman M, Aviram-Goldring A, Izraeli S, Bittner M, Yakhini Z,
Kaminski N. Chromosomal aberrations and gene expression
profiles in non-small cell lung cancer. Lung Cancer. 2007
May;56(2):175-84
Hepatocellular carcinoma
Disease
Proteomic analysis found an overexpression of
RUVBL1 in 4 out of 10 cases (Li et al., 2005).
Autoimmune diseases
Gallant P. Control of transcription by Pontin and Reptin. Trends
Cell Biol. 2007 Apr;17(4):187-92
Disease
Auto-antibodies to RUVBL1 were found in the serum
of patients with polymyositis/dermato-myositis and
autoimmune hepatitis (Makino et al., 1998).
Kim JH, Lee JM, Nam HJ, Choi HJ, Yang JW, Lee JS, Kim
MH, Kim SI, Chung CH, Kim KI, Baek SH. SUMOylation of
pontin chromatin-remodeling complex reveals a signal
integration code in prostate cancer cells. Proc Natl Acad Sci U
S A. 2007 Dec 26;104(52):20793-8
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
255
RUVBL1 (RuvB-like 1 (E. coli))
Haurie V, et al.
Lauscher JC, Loddenkemper C, Kosel L, Gröne J, Buhr HJ,
Huber O. Increased pontin expression in human colorectal
cancer tissue. Hum Pathol. 2007 Jul;38(7):978-85
Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE.
Identification of ATPases pontin and reptin as telomerase
components essential for holoenzyme assembly. Cell. 2008
Mar 21;132(6):945-57
Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR.
Dodecameric structure and ATPase activity of the human
TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92
Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation
in response to DNA damage is modulated by TIP49. Int J
Biochem Cell Biol. 2009 Apr;41(4):925-33
Ducat D, Kawaguchi S, Liu H, Yates JR 3rd, Zheng Y.
Regulation of microtubule assembly and organization in mitosis
by the AAA+ ATPase Pontin. Mol Biol Cell. 2008
Jul;19(7):3097-110
This article should be referenced as such:
Haurie V, Grigoletto A, Rosenbaum J. RUVBL1 (RuvB-like 1
(E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):254-256.
Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum
J. Pontin and reptin, two related ATPases with multiple roles in
cancer. Cancer Res. 2008 Sep 1;68(17):6873-6
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
256
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
RUVBL2 (RuvB-like 2 (E. coli))
Aude Grigoletto, Valérie Haurie, Jean Rosenbaum
INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (AG,
VH, JR)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL2ID42185ch19q13.html
DOI: 10.4267/2042/44704
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
RUVBL2 is phosphorylated on an ATM/ATR
consensus site following DNA damage (Matsuoka et
al., 2007).
Identity
Other names: CGI-46; ECP51; INO80J; REPTIN;
RVB2; Reptin52; Rvb2; TAP54-beta; TIH2; TIP48;
TIP49B
HGNC (Hugo): RUVBL2
Location: 19q13.33
Expression
15 exons, 14 introns (Parfait et al., 2000).
Expression of RUVBL2 is ubiquitous but especially
abundant in thymus and testis (Salzer et al., 1999;
Parfait et al., 2000).
RUVBL2 is overexpressed in hepatocellular carcinoma (Rousseau et al., 2007). Overexpression of
RUVBL2 in several cancers and its possible role in
human cancers has been reported (reviewed in Huber et
al., 2008).
Transcription
Localisation
1518bp mRNA with 463aa open reading frame.
Cytoplasm and nucleus.
DNA/RNA
Description
Function
Protein
RUVBL2 interacts with c-myc (Wood et al., 2000) and
also modulates transcriptional regulation by the betacatenin/TCF-LEF complex (Bauer et al., 2000) and
ATF2 (Cho et al., 2001). RUVBL2 participates in the
remodelling of chromatin as a member of several
complexes such as TIP60 (Ikura et al., 2000), INO80
(Jin et al., 2005), SRCAP (Cai et al., 2005).
It is also involved in transcriptional regulation
(reviewed in Gallant, 2007), DNA repair (Gospodinov
et al., 2008), snoRNP biogenesis (Watkins et al., 2002),
and telomerase activity (Venteicher et al., 2008).
RUVBL2 silencing in fibroblasts induces a senescent
phenotype (Chan et al., 2005).
Description
463 amino acids, 52 kDa.
RUVBL2 belongs to the AAA+ ATPase super-family
(ATPases associated with diverse cellular activities)
sharing conserved Walker A and B motifs, arginine
fingers, and sensor domains. The monomers contain
two domains, which are involved in ATP binding and
hydrolysis respectively. RUVBL2 assembles into an
hexameric structure with a central channel.
RUVBL2 interacts with RUVBL1 to form a dodecamer
(Puri et al., 2007). This RUVBL1/ RUVBL2 complex
displays a significant ATPase activity and is likely one
of the functional forms of the proteins. Sumoylation of
RUVBL2 has been reported on
Lys456 in invasive prostate cancer cells (Kim et al.,
2006).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Implicated in
Hepatocellular carcinoma (HCC)
Disease
257
RUVBL2 (RuvB-like 2 (E. coli))
Grigoletto A, et al.
RUVBL2 was found to be overexpressed in 75% of
cases in a series of 96 human HCC studied with realtime RT-PCR (Rousseau et al., 2007). It was also
increased in a smaller 15 cases series (Iizuka et al.,
2006). No mutations in the coding sequence were
identified (Rousseau et al., 2007).
Prognosis
Overexpression of RUVBL2 was an independent factor
of poor prognosis (Rousseau et al., 2007).
Oncogenesis
RUVBL2 depletion with siRNAs led to HCC cell
growth arrest and apoptosis, whereas over-expression
in HCC cells allowed these cells to give rise to more
progressive tumors in xenografts than control cells
(Rousseau et al., 2007).
Cho SG, Bhoumik A, Broday L, Ivanov V, Rosenstein B, Ronai
Z. TIP49b, a regulator of activating transcription factor 2
response to stress and DNA damage. Mol Cell Biol. 2001
Dec;21(24):8398-413
Colon cancer
Jin J, Cai Y, Yao T, Gottschalk AJ, Florens L, Swanson SK,
Gutiérrez JL, Coleman MK, Workman JL, Mushegian A,
Washburn MP, Conaway RC, Conaway JW. A mammalian
chromatin remodeling complex with similarities to the yeast
INO80 complex. J Biol Chem. 2005 Dec 16;280(50):41207-12
Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of
the box C/D motif is essential for nucleolar localization and is
required, along with the 15.5K protein, for the hierarchical
assembly of the box C/D snoRNP. Mol Cell Biol. 2002
Dec;22(23):8342-52
Cai Y, Jin J, Florens L, Swanson SK, Kusch T, Li B, Workman
JL, Washburn MP, Conaway RC, Conaway JW. The
mammalian YL1 protein is a shared subunit of the
TRRAP/TIP60 histone acetyltransferase and SRCAP
complexes. J Biol Chem. 2005 Apr 8;280(14):13665-70
Chan HM, Narita M, Lowe SW, Livingston DM. The p400 E1Aassociated protein is a novel component of the p53 --> p21
senescence pathway. Genes Dev. 2005 Jan 15;19(2):196-201
Disease
RUVBL2 was overexpressed in a series of 18 colon
cancers (Graudens et al., 2006).
Kim JH, Kim B, Cai L, Choi HJ, Ohgi KA, Tran C, Chen C,
Chung CH, Huber O, Rose DW, Sawyers CL, Rosenfeld MG,
Baek SH. Transcriptional regulation of a metastasis suppressor
gene by Tip60 and beta-catenin complexes. Nature. 2005 Apr
14;434(7035):921-6
Melanoma
Disease
RUVBL2 was overexpressed in a series of 45
melanomas (Talantov et al., 2005).
Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J,
Atkins D, Wang Y. Novel genes associated with malignant
melanoma but not benign melanocytic lesions. Clin Cancer
Res. 2005 Oct 15;11(20):7234-42
Bladder carcinoma
Disease
RUVBL2 was overexpressed in a series of 108 bladder
carcinomas (Sanchez-Carbayo et al., 2006).
Weiske J, Huber O. The histidine triad protein Hint1 interacts
with Pontin and Reptin and inhibits TCF-beta-catenin-mediated
transcription. J Cell Sci. 2005 Jul 15;118(Pt 14):3117-29
Prostate cancer
Graudens E, Boulanger V, Mollard C, Mariage-Samson R,
Barlet X, Grémy G, Couillault C, Lajémi M, Piatier-Tonneau D,
Zaborski P, Eveno E, Auffray C, Imbeaud S. Deciphering
cellular states of innate tumor drug responses. Genome Biol.
2006;7(3):R19
Oncogenesis
In conjunction with beta-catenin, RUVBL2 represses
the expression of the anti-metastasis gene KAI-1 (Kim
et al., 2005) and is involved in the invasive phenotype
of cultured prostate cancer cells (Kim et al., 2006).
Iizuka N, Tsunedomi R, Tamesa T, Okada T, Sakamoto K,
Hamaguchi T, Yamada-Okabe H, Miyamoto T, Uchimura S,
Hamamoto Y, Oka M. Involvement of c-myc-regulated genes in
hepatocellular carcinoma related to genotype-C hepatitis B
virus. J Cancer Res Clin Oncol. 2006 Jul;132(7):473-81
References
Salzer U, Kubicek M, Prohaska R. Isolation, molecular
characterization, and tissue-specific expression of ECP-51 and
ECP-54 (TIP49), two homologous, interacting erythroid
cytosolic proteins. Biochim Biophys Acta. 1999 Sep
3;1446(3):365-70
Kim JH, Choi HJ, Kim B, Kim MH, Lee JM, Kim IS, Lee MH,
Choi SJ, Kim KI, Kim SI, Chung CH, Baek SH. Roles of
sumoylation of a reptin chromatin-remodelling complex in
cancer metastasis. Nat Cell Biol. 2006 Jun;8(6):631-9
Bauer A, Chauvet S, Huber O, Usseglio F, Rothbächer U,
Aragnol D, Kemler R, Pradel J. Pontin52 and reptin52 function
as antagonistic regulators of beta-catenin signalling activity.
EMBO J. 2000 Nov 15;19(22):6121-30
Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, CordonCardo C. Defining molecular profiles of poor outcome in
patients with invasive bladder cancer using oligonucleotide
microarrays. J Clin Oncol. 2006 Feb 10;24(5):778-89
Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J,
Horikoshi M, Scully R, Qin J, Nakatani Y. Involvement of the
TIP60 histone acetylase complex in DNA repair and apoptosis.
Cell. 2000 Aug 18;102(4):463-73
Gallant P. Control of transcription by Pontin and Reptin. Trends
Cell Biol. 2007 Apr;17(4):187-92
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd,
Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal
Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate
analysis reveals extensive protein networks responsive to DNA
damage. Science. 2007 May 25;316(5828):1160-6
Parfait B, Giovangrandi Y, Asheuer M, Laurendeau I, Olivi M,
Vodovar N, Vidaud D, Vidaud M, Bièche I. Human
TIP49b/RUVBL2 gene: genomic structure, expression pattern,
physical link to the human CGB/LHB gene cluster on
chromosome 19q13.3. Ann Genet. 2000 Apr-Jun;43(2):69-74
Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR.
Dodecameric structure and ATPase activity of the human
TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92
Wood MA, McMahon SB, Cole MD. An ATPase/helicase
complex is an essential cofactor for oncogenic transformation
by c-Myc. Mol Cell. 2000 Feb;5(2):321-30
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Rousseau B, Ménard L, Haurie V, Taras D, Blanc JF, MoreauGaudry F, Metzler P, Hugues M, Boyault S, Lemière S, Canron
258
RUVBL2 (RuvB-like 2 (E. coli))
Grigoletto A, et al.
X, Costet P, Cole M, Balabaud C, Bioulac-Sage P, ZucmanRossi J, Rosenbaum J. Overexpression and role of the
ATPase and putative DNA helicase RuvB-like 2 in human
hepatocellular carcinoma. Hepatology. 2007 Oct;46(4):1108-18
Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation
in response to DNA damage is modulated by TIP49. Int J
Biochem Cell Biol. 2009 Apr;41(4):925-33
This article should be referenced as such:
Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum
J. Pontin and reptin, two related ATPases with multiple roles in
cancer. Cancer Res. 2008 Sep 1;68(17):6873-6
Grigoletto A, Haurie V, Rosenbaum J. RUVBL2 (RuvB-like 2
(E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):257-259.
Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE.
Identification of ATPases pontin and reptin as telomerase
components essential for holoenzyme assembly. Cell. 2008
Mar 21;132(6):945-57
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
259
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
SH3GL2 (SH3-domain GRB2-like 2)
Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata 700026, India (CKP,
AG, GPM)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/SH3GL2ID44345ch9p22.html
DOI: 10.4267/2042/44705
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
recycling of synaptic vesicles. SH3GL2 by its LPAAT
activity may induce negative membrane curvature by
converting an inverted cone shaped lipid to a cone
shaped lipid in the cytoplasmic leaflet of the bilayer.
Through this action, SH3GL2 works with dynamin to
mediate synaptic vesicle invagination from the plasma
membrane and fission. SH3GL2 in complex with CBL
and CIN85 participates in activated EGF receptor
(Stimulated by EGF) endocytosis from the membrane
surface and its subsequent lysosomal degradation.
The SH3 domain of SH3GL2 binds to a 24 amino acid
proline rich domain (PRD) in the third intracellular
loop of the G-protein coupled-1-adrenergic receptor.
SH3GL2 overexpression increased isoproterenolinduced receptor inter-nalization by 25% and decreased
coupling of receptor to the G-protein.
The SH3 domain of SH3GL2 also binds to a proline
rich domain within the cytoplasmic tail of metalloprotease disintegrins, transmembrane glycoproteins
acting in cell adhesion and growth factor signaling.
SH3GL2 binds preferentially to the pro-form found in
the trans-Golgi network. Therefore SH3GL2 binding
may regulate intracellular transit and maturation of
metalloprotease disintegrin.
Rat germinal centre kinse-like kinase (rGLK), a
serine/threonine cytosolic kinase, interacted with
SH3GL2. rGLK modulated c-Jun N-terminal kinase
(JNK) activity by phosphorylation and binds to the
SH3 domain of SH3GL2 through a C-terminal proline
rich domain. Coexpression of rGLK and full length
SH3GL2 increased JNK activity two fold, whereas
coexpression with the SH3 domain of SH3GL2
abrogated rGLK-induced JNK activation. SH3GL2,
therefore, modulated the mitogen-activated protein
kinase pathway through physical association with
rGLK.
Identity
Other names: CNSA2; EEN-B1; Endophilin-1;
FLJ20276;
FLJ25015;
OTTHUMP00000021084;
SH3D2A; SH3P4
HGNC (Hugo): SH3GL2
Location: 9p22.2
Local order: Next to ADAMTSL1 and FAN154A.
DNA/RNA
Description
10 exons; spans 217.93kb.
Transcription
mRNA of 2483 and 2417bp (there are two transcripts).
Protein
Description
352 amino acids; 39.96kDa and 330 amino acids;
37.51kDa.
Expression
Highest expression found in brain followed by pituitary
gland and kidney. Expression has also been reported in
bladder, eye, heart, cervix, breast, head and neck
tissues etc.
Localisation
Cytoplasmic (diffuse cytoplasmic distribution in resting
cells and a colocalization with EGF receptor in
endocytic vesicles after EGF stimulation).
Function
SH3GL2 is a presynaptic protein that binds to dynamin,
a GTPase that is implicated in endo-cytosis and
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
260
SH3GL2 (SH3-domain GRB2-like 2)
Panda CK, et al.
Howard L, Nelson KK, Maciewicz RA, Blobel CP. Interaction of
the metalloprotease disintegrins MDC9 and MDC15 with two
SH3 domain-containing proteins, endophilin I and SH3PX1. J
Biol Chem. 1999 Oct 29;274(44):31693-9
Homology
SH3GL2 contains a C-terminal SH3 domain, which
shares 92% and 84% amino acid sequence homology
with the SH3 domain of SH3GL3 and SH3GL1,
respectively. The SH3 domain of SH3GL2 also shows
high homology to the C-terminal SH3 domain of
GRB2.
Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H,
Podtelejnikov AV, Witke W, Huttner WB, Söling HD. Endophilin
I mediates synaptic vesicle formation by transfer of
arachidonate to lysophosphatidic acid. Nature. 1999 Sep
9;401(6749):133-41
Mutations
Tang Y, Hu LA, Miller WE, Ringstad N, Hall
DeCamilli P, Lefkowitz RJ. Identification of
(SH3p4/p8/p13) as novel binding partners
adrenergic receptor. Proc Natl Acad Sci U
26;96(22):12559-64
Somatic
In SH3GL2, mutation in SH3 domain has only been
reported.
RA, Pitcher JA,
the endophilins
for the beta1S A. 1999 Oct
Huttner WB, Schmidt A. Lipids, lipid modification and lipidprotein interaction in membrane budding and fission--insights
from the roles of endophilin A1 and synaptophysin in synaptic
vesicle endocytosis. Curr Opin Neurobiol. 2000 Oct;10(5):54351
Implicated in
Sporadic cancer
Ramjaun AR, Angers A, Legendre-Guillemin V, Tong XK,
McPherson PS. Endophilin regulates JNK activation through its
interaction with the germinal center kinase-like kinase. J Biol
Chem. 2001 Aug 3;276(31):28913-9
Disease
Reduced expressions of SH3GL2 due to different types
of molecular alterations are involved in tumor
formation in head and neck, breast and gastric tissues.
Prognosis
The prognostic significance of down regulation of
SH3GL2 in sporadic tumors is not understood clearly.
Cytogenetics
Chromosomal deletions, chromosomal gain or
amplification and chromosomal breakpoints are
frequent.
Oncogenesis
LOH on 9p22 is one of the most frequent events
identified in head and neck tumor, breast carcinoma,
pituitary adenoma, neuroblastoma etc. However,
promoter methylation appears to be another common
mechanism of SH3GL2 inactivation.
Reutens AT, Begley CG. Endophilin-1: a multifunctional
protein. Int J Biochem Cell Biol. 2002 Oct;34(10):1173-7
Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic
I. Cbl-CIN85-endophilin complex mediates ligand-induced
downregulation of EGF receptors. Nature. 2002 Mar
14;416(6877):183-7
Verstreken P, Kjaerulff O, Lloyd TE, Atkinson R, Zhou Y,
Meinertzhagen IA, Bellen HJ. Endophilin mutations block
clathrin-mediated endocytosis but not neurotransmitter release.
Cell. 2002 Apr 5;109(1):101-12
Chen Y, Deng L, Maeno-Hikichi Y, Lai M, Chang S, Chen G,
Zhang JF. Formation of an endophilin-Ca2+ channel complex
is critical for clathrin-mediated synaptic vesicle endocytosis.
Cell. 2003 Oct 3;115(1):37-48
Hirayama S, Bajari TM, Nimpf J, Schneider WJ. Receptormediated chicken oocyte growth: differential expression of
endophilin isoforms in developing follicles. Biol Reprod. 2003
May;68(5):1850-60
Alzheimer disease
Disease
The increased expression level of SH3GL2 in neuron is
linked to an increase in the activation of the stress
kinase c-Jun N-terminal kinase with the subsequent
death of the neuron.
Prognosis
SH3GL2 overexpression is now considered as a new
indicator of the progression of Alzhemier disease.
Otsuki M, Itoh T, Takenawa T. Neural Wiskott-Aldrich
syndrome protein is recruited to rafts and associates with
endophilin A in response to epidermal growth factor. J Biol
Chem. 2003 Feb 21;278(8):6461-9
Masuda M, Takeda S, Sone M, Ohki T, Mori H, Kamioka Y,
Mochizuki N. Endophilin BAR domain drives membrane
curvature by two newly identified structure-based mechanisms.
EMBO J. 2006 Jun 21;25(12):2889-97
Shang C, Fu WN, Guo Y, Huang DF, Sun KL. Study of the
SH3-domain GRB2-like 2 gene expression in laryngeal
carcinoma. Chin Med J (Engl). 2007 Mar 5;120(5):385-8
Cytogenetics
Increase in aneuploidy or aberration, but chromosomal
loss or gain in aneuploid cell was not specific. In some
forms of Alzheimer disease, a specific type of
aneuploidy-trisomy 21 mosaicism has been reported.
Potter N, Karakoula A, Phipps KP, Harkness W, Hayward R,
Thompson DN, Jacques TS, Harding B, Thomas DG, Palmer
RW, Rees J, Darling J, Warr TJ. Genomic deletions correlate
with underexpression of novel candidate genes at six loci in
pediatric
pilocytic
astrocytoma.
Neoplasia.
2008
Aug;10(8):757-72
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262
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
TOPORS (topoisomerase I binding,
arginine/serine-rich)
Jafar Sharif, Asami Tsuboi, Haruhiko Koseki
Developmental Genetics Group, RIKEN Center for Allergy and Immunology (RCAI), Suehirocho 1-7-22,
Tsurumi-ku, Yokohama-shi, Kanagawa-ken, Japan 230-0045 (JS, AT, HK)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TOPORSID42663ch9p21.html
DOI: 10.4267/2042/44706
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pseudogene
Identity
None reported.
Other
names:
EC
6.3.2.-;
LUN;
OTTHUMP00000021182; OTTHUMP00000021184;
OTTHUMP00000045227; P53BP3; RP31; TP53BPL;
p53BP3
HGNC (Hugo): TOPORS
Location: 9p21.1
Protein
Description
TOPORS transcript 1 encodes a protein containing
1,045 amino acids (ENSP00000353735).
TOPORS transcript 2 encodes a protein containing 980
amino acids (ENSP00000369187).
The 1045aa human TOPORS contains a RING family
zinc-finger domain and a leucine zipper (LZ) domain in
the N-terminal. It also possesses a C-terminal bipartite
nuclear localization signal (NLS), five sequences rich
in proline, glutamine, serine and threonine (PEST
sequences) and an arginine rich domain.
DNA/RNA
Description
Spans approximately 8kbs of DNA in the reverse strand
of chromosome 9.
Transcription
Two splicing variants.
Transcript 1 (ENST00000360538): Transcript length
4145 bps, three exons, first one non-coding.
Transcript 2 (ENST00000379858): Transcript length
3,621 bps, two exons, first one non-coding.
Expression
Widely expressed.
Localisation
Nucleus.
The two splicing variants of TOPORS are shown. Transcript 1 (ENST00000360538) has three exons, the first one non-coding. Transcript
2 (ENST00000379858) has two exons, the first one non-coding. The coding regions are shown in yellow boxes and the non-coding
regions (untranslated regions, UTRs) are shown in open boxes.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
263
TOPORS (topoisomerase I binding, arginine/serine-rich)
Sharif J, et al.
dominant retinitis pigmentosa (Bowne et al., 2008).
Another study reported that mutations in TOPORS
cause autosomal dominant retinitis pigmentosa with
perivascular retinal pigment epithelium atrophy
(Chakarova et al., 2007).
Valuable information on the cellular roles for TOPORS
came through several biochemical studies. It was
shown that in the nucleus TOPORS undergoes SUMO1 modifications (Weger et al., 2003). Interestingly,
TOPORS itself has the ability to sumoylate other
proteins by functioning as a SUMO-1 E3 ligase. For
example, TOPORS can sumoylate p53 and the
chromatin modifying protein Sin3A (Shinbo et al.,
2005; Weger et al., 2005; Pungaliya et al., 2007).
Furthermore, TOPORS induce the accumulation of
polysumoylated forms of DNA topoisomerase I in vitro
and in vivo (Hammer et al., 2007). Intriguingly, apart
from its role as a SUMO-1 E3 ligase, TOPORS can
also function as an E3 ubiquitin ligase. In fact,
TOPORS was the first example of a protein that
possesses dual-roles as an E3 ligase for sumoylation
and ubiquitination of other proteins. It was reported
that Topors works as an E3 ubiquitin ligase with
specific E2 enzymes to ubiquitinate the p53 protein and
the prostrate tumor suppressor protein NKX3.1
(Rajendra et al., 2004; Guan et al., 2008). Intense
investigations have been undertaken in recent years to
elucidate the mechanisms of molecules that have dual
E3 ligase activities for sumoylation and ubiquitination
such as TOPORS. These studies have discovered a new
family of proteins, designated as the small ubiquitinrelated modifier (SUMO)-targeted ubiquitin ligases
(STUbLs), which directly links sumoylation and
ubiquitination (Perry et al., 2008). It has been
suggested that similar to STUbLs, TOPORS may be
recruited to its targets through SUMO-associated
interactions and stimulate their ubiquitination in a
RING finger-dependent manner (Perry et al., 2008).
Furthermore, TOPORS has been connected with
transcriptional regulation because of its role as an E3
ubiquitin ligase. In drosophila, the homolog of human
TOPORS (dTopors) ubiquitinates the Hairy
transcriptional repressor, suggesting that TOPORS
could be involved in regulating other transcription
factors as well (Secombe et al., 2004). Indeed, it was
shown that TOPORS interacts with the adenoassociated virus type 2 (AAV-2) Rep78/68 proteins and
enhances the expression of a Rep78/68 dependent
AAV-2 gene in the absence of the helper virus (Weger
et al., 2002). Finally, it was shown that drosophila
dTopors was required for the nuclear organization of a
chromatin insulator, suggesting a role for TOPORS in
regulation of the chromatin (Capelson et al., 2005).
Homology between murine Topors and human TOPORS is
shown. The N-terminal Ring-finger (RF, red) and leucine zipper
(LZ, green) domains show 93% homology and the C-terminal
nuclear localization signal (NLS, blue) domain shows 90%
homology between mouse and human. The P53 binding
regions of TOPORS, located inside the NLS domain, are
highlighted with red lines.
Function
The RING finger protein TOPORS contains a RING
family zinc-finger domain, a putative leucine zipper
(LZ) domain, five sequences rich in proline, glutamine,
serine and threonine (PEST sequences), an
arginine/serine (RS) domain and a bipartite nuclear
localization signal (NLS). TOPORS was first identified
as a human topoisomerase I-interacting protein by yeast
two-hybrid screening (Haluska et al., 1999). TOPORS
is localized in the nucleus and has been reported to be
closely associated with the PML bodies (Weger et al.,
2003; Rasheed et al., 2002). An important role of
TOPORS is its ability to interact with the tumor
suppressor protein P53 (Zhou et al., 1999). Forced
expression of murine Topors during DNA damage
stabilizes
p53,
enhances
the
p53-dependent
transcriptional activities of waf1, MDM2 and Bax
promoters and elevates the level of endogenous p21 waf1
mRNA (Lin et al., 2005). These findings suggest an
anti-oncogenic role for TOPORS. Indeed, it was shown
that TOPORS expression is decreased or undetectable
in colon adenocarcinomas relative to normal colon
tissue, and the protein level of TOPORS is undetected
in several colon cancer cell lines (Saleem et al., 2004).
Repression of TOPORS expression was also reported
in progression and development of non-small cell lung
cancer (Oyanagi et al., 2004).
Furthermore, loss of heterozygosity in the region 9p21,
the chromosomal locus harboring TOPORS, has been
frequently associated with different malignancies (Puig
et al., 2005). A high-resolution genomewide mapping
study identified deletion of the TOPORS genomic
locus in human glial tumors, suggesting a possible role
for TOPORS in gliomagenesis (Bredel et al., 2005). A
missense mutation in the TOPORS gene was
implicated in autosomal dominant pericentral retinal
dystrophy, showing that mutations in the TOPORS
gene can lead to genetic disorders (Selmer et al., 2009).
Concomitant with these observations, point mutations
and small insertions and deletions in the TOPORS gene
was found to cause approximately 1% of autosomal
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Homology
Widely conserved among different species. Murine
Topors shows high similarity with human TOPORS.
264
TOPORS (topoisomerase I binding, arginine/serine-rich)
Sharif J, et al.
gene expression was down-regulated in smokers
(Oyanagi et al., 2004). These findings show that there
is a reverse correlation between NSCLC and TOPORS
expression and suggest that TOPORS may act as a
tumor sup-pressor gene for lung cancers.
Mutations
Germinal
TOPORS has been implicated in autosomal dominant
pericentral retinal dystrophy (adPRD), an atypical form
of retinitis pigmentosa. Retinitis pigmentosa is the
collective name for a group of genetically induced eye
disorders that are frequenctly associated with night
blindness and tunnel vision. The TOPORS gene was
sequenced in 19 affected members of a large
Norwegian family. A novel missense mutation,
c.1205a>c, resulting in an amino acid substitution
p.Q402P, was found in all of the cases. Furthermore,
the mutation showed complete co-segregation with the
disease in the family, with the LOD score of 7.3. This
mutation was not detected in 207 unrelated and healthy
Norwegian subjects (Selmer et al., 2009). A separate
study showed that mutations in the TOPORS gene are
responsible for autosomal dominant retinitis
pigmentosa (adRP). Mutations that included an
insertion and a deletion were identified in two adRPaffected families (Chakarova et al., 2007). Finally,
another recent study investigated whether mutation(s)
in the TOPORS gene is associated with autosomal
dominant retinitis pigmentosa (adRP). The frequency
of TOPORS mutation was analyzed in an adRP cohort
of 215 families and two different mutations, namely,
p.Glu808X and p.Arg857GlyfsX9, were identified.
This study concluded that point mutations and small
insertions or deletions in TOPORS may cause
approximately 1% of adRP (Bowne et al., 2008).
Glial brain tumor
Disease
Glial brain tumors arise from glial cells and are highly
lethal. Glial brain tumors include astrocytomas,
oligodendrogliomas and oligoastro-cytomas.
Oncogenesis
A recent study investigated copy number alterations of
42,000 mapped human cDNA clones in a series of 54
gliomas of varying histogenesis and tumor grade by
comparative genomic hybridization technology. This
study reported a set of genetic alterations
predominantly associated with either astrocytic or
oligodendrocytic tumor phenotype. Among these
genetic alterations, a minimally deleted region
containing the TOPORS gene was identified,
suggesting a role for TOPORS in gliomagenesis
(Bredel et al., 2005).
Colon cancer
Disease
Cancerous growth in colon, rectum or the appendix are
collectively addressed as colon cancer or colorectal
cancer. This is the third most frequent form of cancer
and a major cause of cancer-related death all over the
world.
Oncogenesis
TOPORS expression is decreased or undetected in
colon adenocarcinomas compared to normal colon
tissues. Furthermore, TOPORS protein is not detectable
in several colon cancer cell lines, suggesting an antioncogenic role for TOPORS (Saleem et al., 2004).
Implicated in
Non-small cell lung cancer (NSCLC)
Disease
Non-small cell lung cancer (NSCLC) is the major form
of lung cancer, with a frequency of 80~90% of all lung
carcinomas. NSCLCs are usually classified into three
groups,
namely,
squamous
cell
carcinoma,
adenocarcinoma and large-cell carci-noma. The
squamous cell carcinoma is linked with smoking and
accounts for approximately 25~30% of all lung
cancers, which are usually found in the middle of the
lungs or near a bronchus. Adenocarci-noma is
frequently spotted in the outer part of the lungs and is
thought to be responsible for ~40% of all lung cancers.
About 10~15% of lung cancers are large-cell
carcinomas, which can start in any part of the lung and
has the ability to grow and spread quickly, making this
type of lung cancers difficult to treat.
Oncogenesis
Expression of TOPORS was found to be signifi-cantly
repressed in lung cancer tissues compared to normal
lung tissues. TOPORS gene expression was slightly
down-regulated along with progression of primary
tumors, and strongly downregulated along with nodal
metastases. Interestingly, in normal tissues TOPORS
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Autosomal dominant retinitis
pigmentosa (adRP)
Disease
Autosomal dominant retinitis pigmentosa (adRP) is a
form of retinitis pigmentosa, a collective title for a
group of genetically induced eye disorders that are
frequenctly associated with night blindness and tunnel
vision.
Prognosis
Mutations and small insertions or deletions of the
TOPORS gene have been associated with adRP.
TOPORS has been associated with autosomal dominant
pericentral retinal dystrophy (adPRD), which has a
favorable prognosis compared to classical retinitis
pigmentosa (RP). A novel mis-sense mutation,
c.1205a>c, resulting in an amino acid substitution
p.Q402P, was observed in all affected members of a
large Norweigian family (Selmer et al., 2009). In
another study, an adRP cohort of 215 families was
investigated and two different mutations, namely,
265
TOPORS (topoisomerase I binding, arginine/serine-rich)
Sharif J, et al.
Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD,
Sikic BI. High-resolution genome-wide mapping of genetic
alterations in human glial brain tumors. Cancer Res. 2005 May
15;65(10):4088-96
p.Glu808X and p.Arg857GlyfsX9, were identified
(Bowne at al., 2008). TOPORS has also been
implicated in autosomal dominant retinitis pigmentosa
with perivascular retinal pigment atrophy, a disorder
that showed a distinct phenotype at the earlier stage of
the disease, with an unusual perivascular cuff of retinal
pigment epithelium atrophy, which was found
surrounding the superior and inferior arcades in the
retina. This study reported mutations in the TOPORS
gene that included an insertion and a deletion was
identified in two adRP-affected families (Chakarova et
al., 2007).
Capelson M, Corces VG. The ubiquitin ligase dTopors directs
the nuclear organization of a chromatin insulator. Mol Cell.
2005 Oct 7;20(1):105-16
Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A,
Zhang JH, Simonds WF, Nakagawara A, Koseki H. topors, a
p53 and topoisomerase I-binding RING finger protein, is a
coactivator of p53 in growth suppression induced by DNA
damage. Oncogene. 2005 May 12;24(21):3385-96
Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1
restores p53 transcription activity inhibited by Topors/p53BP3.
Int J Oncol. 2005 Mar;26(3):641-8
References
Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1
E3 ligase for p53 in vitro and in vivo. FEBS Lett. 2005 Sep
12;579(22):5007-12
Puig S, Ruiz A, Lázaro C, Castel T, Lynch M, Palou J, Vilalta
A, Weissenbach J, Mascaro JM, Estivill X. Chromosome 9p
deletions in cutaneous malignant melanoma tumors: the
minimal deleted region involves markers outside the p16
(CDKN2) gene. Am J Hum Genet. 1995 Aug;57(2):395-402
Zhou R, Wen H, Ao SZ. Identification of a novel gene encoding
a p53-associated protein. Gene. 1999 Jul 22;235(1-2):93-101
Chakarova CF, Papaioannou MG, Khanna H, Lopez I,
Waseem N, Shah A, Theis T, Friedman J, Maubaret C,
Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott de Q,
Parapuram SK, Bickmore WA, Munro PM, Gal A, Hamel CP,
Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K,
Swaroop A, Koenekoop RK, Bhattacharya SS. Mutations in
TOPORS cause autosomal dominant retinitis pigmentosa with
perivascular retinal pigment epithelium atrophy. Am J Hum
Genet. 2007 Nov;81(5):1098-103
Rasheed ZA, Saleem A, Ravee Y, Pandolfi PP, Rubin EH. The
topoisomerase I-binding RING protein, topors, is associated
with promyelocytic leukemia nuclear bodies. Exp Cell Res.
2002 Jul 15;277(2):152-60
Hammer E, Heilbronn R, Weger S. The E3 ligase Topors
induces the accumulation of polysumoylated forms of DNA
topoisomerase I in vitro and in vivo. FEBS Lett. 2007 Nov
27;581(28):5418-24
Weger S, Hammer E, Heilbronn R. Topors, a p53 and
topoisomerase I binding protein, interacts with the adenoassociated virus (AAV-2) Rep78/68 proteins and enhances
AAV-2 gene expression. J Gen Virol. 2002 Mar;83(Pt 3):511-6
Pungaliya P, Kulkarni D, Park HJ, Marshall H, Zheng H,
Lackland H, Saleem A, Rubin EH. TOPORS functions as a
SUMO-1 E3 ligase for chromatin-modifying proteins. J
Proteome Res. 2007 Oct;6(10):3918-23
Oyanagi H, Takenaka K, Ishikawa S, Kawano Y, Adachi Y,
Ueda K, Wada H, Tanaka F. Expression of LUN gene that
encodes a novel RING finger protein is correlated with
development and progression of non-small cell lung cancer.
Lung Cancer. 2004 Oct;46(1):21-8
Bowne SJ, Sullivan LS, Gire AI, Birch DG, HughbanksWheaton D, Heckenlively JR, Daiger SP. Mutations in the
TOPORS gene cause 1% of autosomal dominant retinitis
pigmentosa. Mol Vis. 2008 May 19;14:922-7
Haluska P Jr, Saleem A, Rasheed Z, Ahmed F, Su EW, Liu LF,
Rubin EH. Interaction between human topoisomerase I and a
novel RING finger/arginine-serine protein. Nucleic Acids Res.
1999 Jun 15;27(12):2538-44
Guan B, Pungaliya P, Li X, Uquillas C, Mutton LN, Rubin EH,
Bieberich CJ. Ubiquitination by TOPORS regulates the
prostate tumor suppressor NKX3.1. J Biol Chem. 2008 Feb
22;283(8):4834-40
Rajendra R, Malegaonkar D, Pungaliya P, Marshall H,
Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A, Rubin
EH. Topors functions as an E3 ubiquitin ligase with specific E2
enzymes and ubiquitinates p53. J Biol Chem. 2004 Aug
27;279(35):36440-4
Perry JJ, Tainer JA, Boddy MN. A SIM-ultaneous role for
SUMO and ubiquitin. Trends Biochem Sci. 2008
May;33(5):201-8
Saleem A, Dutta J, Malegaonkar D, Rasheed F, Rasheed Z,
Rajendra R, Marshall H, Luo M, Li H, Rubin EH. The
topoisomerase I- and p53-binding protein topors is differentially
expressed in normal and malignant human tissues and may
function as a tumor suppressor. Oncogene. 2004 Jul
8;23(31):5293-300
Selmer KK, Grøndahl J, Riise R, Brandal K, Braaten O,
Bragadottir R, Undlien DE. Autosomal dominant pericentral
retinal dystrophy caused by a novel missense mutation in the
TOPORS gene. Acta Ophthalmol. 2010 May;88(3):323-8
This article should be referenced as such:
Secombe J, Parkhurst SM. Drosophila Topors is a RING
finger-containing protein that functions as a ubiquitin-protein
isopeptide ligase for the hairy basic helix-loop-helix repressor
protein. J Biol Chem. 2004 Apr 23;279(17):17126-33
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Sharif J, Tsuboi A, Koseki H. TOPORS (topoisomerase I
binding, arginine/serine-rich). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(3):263-266.
266
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
TRPV6 (transient receptor potential cation
channel, subfamily V, member 6)
Yoshiro Suzuki, Matthias A Hediger
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern,
Switzerland (YS, MAH)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TRPV6ID44425ch7q34.html
DOI: 10.4267/2042/44707
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
The regions encoding the ankyrin repeats, 6 transmembrane domains and a pore region are indicated.
Several VDREs (vitamin D responsive element) have
been identified in its promoter region.
A
haplotype
containing
3
non-synonymous
polymorphisms (C157R+M378V+M681T) repre-sent a
recent positive selection in human evolution. The same
haplotype seems to be associated with renal calcium
stone formation.
Identity
Other names: CaT1; ECaC2; CATL; ABP/ZF;
LP6728; ZFAB
HGNC (Hugo): TRPV6
Location: 7q34
Local order: Colocalized with another Ca2+-selective
epithelial channel gene, TRPV5.
Transcription
DNA/RNA
There is an alterative splice variant which missed 25192 (a.a.). In EST database, there seems to be at least
one more variant using different exon 1 (V2) and a
variant starting from another site (P3) just upstream of
exon 2 (V3).
Description
TRPV6 gene consists of 15 exons and 14 introns
including a coding, and a 5'-/3'- non-coding region.
Schematic representation of human TRPV6 gene and neighbouring genes.
Genomic structure of human TRPV6. The coding region is shown by open bars. The non-translated regions are shown by filled bars.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
267
TRPV6 (transient receptor potential cation channel, subfamily V, member 6)
Suzuki Y, Hediger MA
increase in proliferation and apoptotic resistance in
cancer cells.
Homology
Protein
73% identity with human TRPV5. 89% identity with
mouse TRPV6.
Implicated in
Prostate cancer
Oncogenesis
Expression of TRPV6 may be a predictor for prostate
cancer progression since TRPV6 mRNA and protein
levels are elevated in prostatic carcinoma compared to
benign prostatic hyperplasia and positively correlated
with Gleason grade/score in prostatic carcinoma.
TRPV6 is involved in an increase in proliferation and
apoptotic resistance in cancer cells, suggesting that
TRPV6 could be a new therapeutic target for the
treatment for advanced prostate cancer.
Schematic representation of TRPV6 protein. Four subunits
makes one channel pore. Several ankyrin repeats, one Nglycosylation site and several calmodulin binding sites (CaM)
are indicated.
Breast cancer
Description
Oncogenesis
TRPV6 mRNA was also found to be increased in breast
cancer tissues compared to normal breast tissues.
TRPV6 could be a prognostic marker for breast cancer
and therapeutic target for breast cancer treatment.
Glycosylated membrane protein (725 a.a., MW ~70
kDa) with 6 transmembrane regions and a pore-forming
loop. N- and C-terminal tails are in cytoplasmic side.
This protein forms a Ca2+-selective ion channel in the
plasma
membrane.
TRPV6 interacts with
References
calmodulin which contribute to the intracellular
Ca2+-dependent inactivation to avoid an increase
of free Ca2+ concentration. The ankyrin repeats
may play a role in the interaction between
subunits. TRPV6 can form a homo-tetramer as
well as a hetero-tetramer with TRPV5, which
exhibits distinct channel properties.
Hediger MA, Peng JB, Brown EM Inventors.. Compositions
Corresponding to a Calcium Transporter and Methods of
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Expression
Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC,
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Highly expressed in placenta, moderately expressed in
exocrine pancreas, mammary gland and salivary gland.
Highly induced in small intestine under low calcium
conditions or by 1,25-dihydroxyvitamin D3 treatment.
Highly induced in prostate, breast and other cancer
tissues during tumor progression.
Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C.
Competitive regulation of CaT-like-mediated Ca2+ entry by
protein kinase C and calmodulin. Proc Natl Acad Sci U S A.
2001 Mar 13;98(6):3600-5
Localisation
Peng JB, Brown EM, Hediger MA. Structural conservation of
the genes encoding CaT1, CaT2, and related cation channels.
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Plasma membrane. Localized in the apical membrane
of the epithelial cells in the duodenum, and
syncytiotrophoblasts in placenta.
Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown
EM, Hediger MA, Freeman MR. CaT1 expression correlates
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Function
Apical Ca2+ entry pathway for total body calcium
homeostasis in the small intestine under the control of
1,25-dihydroxyvitamin D3. TRPV6 likely also be
involved in the placental Ca2+ transport from mother to
fetus to maintain fetal bone mineralization.
TRPV6 may play a role in the Ca2+ entry pathway
essential for keratinocyte differentiation. Although its
exact function in cancer cells and tumor progression is
still under investigation, TRPV6 is involved in an
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans
I, Van Herck E, Kato S, Bindels RJ, Collen D, Carmeliet P,
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Suzuki Y, Hediger MA
Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos
CH, Zhuang L, Freeman MR, Gouveia CH, Wu J, Luo H,
Mauro T, Brown EM, Hediger MA. Marked disturbance of
calcium homeostasis in mice with targeted disruption of the
Trpv6 calcium channel gene. J Bone Miner Res. 2007
Feb;22(2):274-85
Nilius B, Prenen J, Hoenderop JG, Vennekens R, Hoefs S,
Weidema AF, Droogmans G, Bindels RJ. Fast and slow
inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2
(TRPV5 and TRPV6). Role of the intracellular loop located
between transmembrane segments 2 and 3. J Biol Chem.
2002 Aug 23;277(34):30852-8
Lehen'kyi V, Beck B, Polakowska R, Charveron M, Bordat P,
Skryma R, Prevarskaya N. TRPV6 is a Ca2+ entry channel
essential for Ca2+-induced differentiation of human
keratinocytes. J Biol Chem. 2007 Aug 3;282(31):22582-91
Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger
MA, Freeman MR. Calcium-selective ion channel, CaT1, is
apically localized in gastrointestinal tract epithelia and is
aberrantly expressed in human malignancies. Lab Invest. 2002
Dec;82(12):1755-64
Lehen'kyi V, Flourakis M, Skryma R, Prevarskaya N. TRPV6
channel controls prostate cancer cell proliferation via
Ca(2+)/NFAT-dependent pathways. Oncogene. 2007 Nov
15;26(52):7380-5
Fixemer T, Wissenbach U, Flockerzi V, Bonkhoff H.
Expression of the Ca2+-selective cation channel TRPV6 in
human prostate cancer: a novel prognostic marker for tumor
progression. Oncogene. 2003 Oct 30;22(49):7858-61
Bolanz KA, Hediger MA, Landowski CP. The role of TRPV6 in
breast carcinogenesis. Mol Cancer Ther. 2008 Feb;7(2):271-9
Hughes DA, Tang K, Strotmann R, Schöneberg T, Prenen J,
Nilius B, Stoneking M. Parallel selection on TRPV6 in human
populations. PLoS One. 2008 Feb 27;3(2):e1686
Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius
B, Bindels RJ. Homo- and heterotetrameric architecture of the
epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J. 2003
Feb 17;22(4):776-85
Stumpf T, Zhang Q, Hirnet D, Lewandrowski U, Sickmann A,
Wissenbach U, Dörr J, Lohr C, Deitmer JW, Fecher-Trost C.
The human TRPV6 channel protein is associated with
cyclophilin B in human placenta. J Biol Chem. 2008 Jun
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Suzuki Y, Hediger MA. TRPV6 (transient receptor potential
cation channel, subfamily V, member 6). Atlas Genet
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269
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
ADAM9 (ADAM metallopeptidase domain 9
(meltrin gamma))
Shian-Ying Sung
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and
Hospital, Taichung, Taiwan (SYS)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/ADAM9ID573ch8p11.html
DOI: 10.4267/2042/44708
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
mitotic arrest deficient 2beta. ADAM9 has implicated
mediated by stress, such as oxidation during
inflammation and cancer progression.
Identity
Other names: MDC9; Meltrin-gamma; MLTNG;
MCMP; KIAA0021
HGNC (Hugo): ADAM9
Location: 8p11.23
Local order: TACC1 - PLEKHA2 - HTRA4 - TM2D2
- ADAM9 - ADAM32 - ADAM5p - ADAM3A ADAM18 - ADAM2; TACC1; 8P11; Transforming,
acidic coiled-coil containing protein 1; PLEKHA2;
8P11.23; Pleckstrin homology domain containing,
family A member 2; HTRA4; 8P11.23; HtrA serine
peptidase 4; TM2D2; 8P11.23; TM2 domain containing
2;
ADAM9;
8P11.23;
a
disintegrin
and
metalloproteinase domain 9; ADAM32; 8p11.23;
ADAM metalloproteinase domain 32; ADAM5P;
8p11.23; ADAM metallopeptidase domain 5
pseudogene;
ADAM3A;
8p11.23;
ADAM
metallopeptidase domain 3A (Cyritestin 1); ADAM18;
8p11.22; ADAM metallopeptidase domain 18;
ADAM2; 8p11.22; ADAM metallopeptidase domain 2.
Note
The ADAM9 gene, a member of the ADAM superfamily has metalloprotease, integrin binding and cell
adhesion capacities. It shown the metallo-protease
domain cleaves insulin beta-chain, TNF-alpha, gelatin,
beta-casein, fibronectin, as well as shedding of EGF,
HB-EGF and FGFR2IIIB. The integrin domain
mediates cellular adhesion through alpha6beta1 and
alphavbeta5 integrins. The cytoplasmic tail of ADAM9
has been reported to interact with endophilin 1
(SH3GL2), SH3PX1 and
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
DNA/RNA
Note
The ADAM9 gene transcript 2 isoforms of mRNA with
altered splicing results the lost of exon 18 in the second
isoform of ADAM9 mRNA and early stop codon.
Description
ADAM9 gene extends 108,276 base pairs with 22
exons which gives rise to 2 different ADAM9 transcripts with differential splicing. The mRNA of
ADAM9 isoform 1 is 4111 base pair and isoform 2 is
4005. ADAM9 isoform 2 lacks exon 18 of iso-form 1
in the coding region, which results in a frameshift and
an early stop codon. The isoform 2 lacks the c-terminal
transmembrane and cyto-plasmic domains and is a
secreted form.
Transcription
Isoform 1 mRNA of ADAM9 (NM_003816) has a size
of 4111 bp, isoform 2 mRNA (NM_001005845) has a
size of 4005 bp. ADAM9 mRNA is equally expressed
in many tissue. Among cancer progression, ADAM9
mRNA is relatively highly expressed in prostate cancer
and breast cancer. However, little is known of
differential expression between different isoform of
ADAM9.
Pseudogene
No pseudogene has reported for ADAM9.
270
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))
Sung SY
ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of
ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2
carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop
translation in exon 19.
alteration and lost of exon 18 of ADAM9 causes lost of
transmembrane domain and early stop in soluble form
of ADAM9.
Protein
Note
Two different isoform of ADAM9 was reported, the
full length and soluble form of ADAM9. Recent report
suggests promoter polymorphisms regulated ADAM9
transcription that plays a protective role against
Alzheimer's disease.
Localisation
Full length has N-terminal signal peptide and a single
hydrophobic region predicted to be transmembrane
domain. Hence, the full length of ADAM9 is localized
to the plasma membrane. Soluble ADAM9 lack the
transmembrane domain and cytoplasmic domain and to
be released out of cell.
Description
The predicted molecular mass of ADAM9 is about 84
KDa. ADAM9 contained coding sequence of 2460
nucleotides which encoding amino acid of 819
residues. The full length of active ADAM9 contained
several functional regions including metalloproteinase,
disintegrin, cystein rich, EGF-like, transmembrane and
cytoplasmic domains. The pro-domain of ADAM9 was
removed by furin-type convertase during ADAM9
translocated onto membrane and become active form.
Recent reports indicated soluble form of ADAM9
cloned from human cDNA library that showed
increased of cancer invasion in malignant progression.
Function
1. Ectodomain shedding: Metalloproteinase domain of
ADAM9 is zinc dependent. Metallo-proteinase has
been showed to involve ectodomain shedding (see table
below). One such protein is the heparin-binding EGFlike growth factor (HB-EGF) and amyloid precursor
protein (APP).
2. Matrix Degradation: purified metalloproteinase
domain of ADAM9 showed the ability to digest
fibronectin, gelatin and beta-casein. Secreted form of
ADAM9 showed the ability to digest laminin and
promote cancer invasion.
3. Cell contact: ADAM9 specifically bind to integrin
alpha6beta1, a laminin receptor, via disintegrin region of
ADAM9 through non-RGD mechanism. ADAM9 also
have been implicated in binding of a vbeta5 in divalent
cation dependent condition, suggests ADAM9 can
function as adhesion molecule for cell-cell and cellmartrix interaction. Secreted form of ADAM9 binds
directly to alpha6beta4 and alpha2beta1 integrin and
Expression
ADAM9 is ubiquitously expressed. SAGE analyses of
ADAM9 expression demonstrated that ADAM9 is
expressed in the bone marrow, lymph node, brain,
retina, heart, skin, muscle, lung, prostate, breast and
placenta. Increased expression of ADAM9 was
reported in several cancers, including gastric, breast,
prostate, colon, and pancreatic cancers. Splicing
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
271
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))
Sung SY
Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or
neighbor cell.
ability to cleave laminin and promote cancer
progression.
4. Cysteine-Rich domain: The ADAM Cysteine-rich
domain is not found in other organisms, such as virus,
archaeal, bacterial or plant. The function of cysteinerich domain might involved in complement the binding
ability of disintegrin-mediated interactions.
Homology
The table below gives homology between the human
ADAM9 and others organisms.
Mutations
Note
Single nucleotide polymorphosim analyses of
chromosome 8 demonstrated about 356 SNP in the
chromosome 8p11.23. Most of them are located in
intron of ADAM9. No mutation was reported in
ADAM9 coding sequence. Recent evidence sug-gests
promoter polymorphisms that may upregulate ADAM9
transcription, such as -1314C has higher of
transcription activities.
TABLE: Substrate and Peptide Sequence Cleaved.
Substrate
Peptide sequence cleaved
(*: cleave site)
Amyloid
precursor
protein
EVHH*QKLVFFAE
TNF-a
SPLA*QAVRS*SSR
P75
TNF
SMAPGAVH*LPQP
receptor
c-kit ligand
Insulin
Chain
HB-EGF
LPPVA*A*S*SLRND
B
LVEALY*LVCGERGFFY*TPKA
GLSLPVE*NRLYTYD
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
272
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))
Sung SY
ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9
transcription compared to 1314T.
Implicated in
demonstrated copy number abnormalities occurred in
ADAM9 gene.
Prostate cancer
Lung cancer
Note
ADAM9 has been implicated in prostate cancer
progression and the production of reactive oxygen
species. Large cohort of clinic evaluation demonstrated ADAM9 is upregulated in prostate cancer in both
mRNA and protein level. ADAM9 protein expression
can be upregulated by androgen in AR-positive but not
in AR-negative prostate cancer cells that is through
downstream ROS as mediator to induce ADAM9
expression. ADAM9 protein expression is associated
with shortened PSA-relapse-free survival in clinic
evaluation.
Note
The increased of ADAM9 expression in lung cancer
enhanced cell adhesion and invasion of non-small cell
lung cancer through change adhesion properties and
sensitivity to growth factors, and increase its capacity
of brain metastasis.
Renal cell carcinoma
Note
ADAM9 was implicated increased expression in renal
cell carcinoma and associated with tumor progression.
It also showed higher of ADAM9 expression is
associated with shorten patient survival rate.
Pancreatic cancer
Alzheimer's disease
Note
Pancreatic ductal adenocarcinomas showing increased
of ADAM9 expression in microarray analyses and
clinic evaluation that correlated with poor tumor
differentiation and shorter overall survival rate.
Note
The amyloid precursor protein (APP) of Alzheimer's
disease is a transmembrane protein processed via either
the non-amyloidogenic or amyloidogenic pathways. In
the non-amyloidogenic pathway, alpha-secretase
cleaves APP within the Abeta peptide region releasing
a large soluble fragment sAPPalpha that has
neuroprotective properties. In the amyloidogenic
pathway,
beta-secretase
and
gamma-secretase
sequentially cleave APP to generate the intact Abeta
peptide, which is neurotoxic.
Breast cancer
Note
ADAM9 expression is 24% positive in normal breast
tissue and 66% positive in breast carcinomas. Western
blot studies demonstrated multiform of ADAM9 were
expressed in breast carcinoma. In addition, recent study
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
273
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))
Sung SY
Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. Critical
function for ADAM9 in mouse prostate cancer. Cancer Res.
2005 Oct 15;65(20):9312-9
In ADAM9 expression analyses showed increase in
production of sAPPalpha upon phorbol ester treatment
of cell that co-express of ADAM9 and APP. ADAM9
did not cleave at the Lys16-Leu17 bone but at the
His14-Gln15 bone in the Abeta domain of APP cleave
site. Hence, ADAM9 might play role in protective
against sporadic Alzheimer's disease.
Chin K, DeVries S, Fridlyand J, Spellman PT, et al. Genomic
and transcriptional aberrations linked to breast cancer
pathophysiologies. Cancer Cell. 2006 Dec;10(6):529-41
Hirao T, Nanba D, Tanaka M, Ishiguro H, Kinugasa Y, Doki Y,
Yano M, Matsuura N, Monden M, Higashiyama S.
Overexpression of ADAM9 enhances growth factor-mediated
recycling of E-cadherin in human colon cancer cell line HT29
cells. Exp Cell Res. 2006 Feb 1;312(3):331-9
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Oxidative stress induces ADAM9 protein expression in human
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human ADAM9 has an alpha-secretase activity for APP.
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F, Alldinger I, Kersting S, Ockert D, Koch R, Kalthoff H,
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Sung SY. ADAM9 (ADAM metallopeptidase domain 9 (meltrin
gamma)). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):270-274.
274
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
CYP7B1 (cytochrome P450, family 7, subfamily B,
polypeptide 1)
Maria Norlin
Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Sweden (MN)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/CYP7B1ID40255ch8q21.html
DOI: 10.4267/2042/44709
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pseudogene
Identity
No pseudogenes reported.
Other names: CBAS3; CP7B; SPG5A; CYP7B
HGNC (Hugo): CYP7B1
Location: 8q21.3
Note
CYP7B1 is a steroid hydroxylase involved in metabolism of sex hormones, oxysterols (a type of
cholesterol derivatives) and neurosteroids.
Protein
Description
The human CYP7B1 protein consists of 506 amino
acids and has a molecular weight of 58,256. The Nterminal membrane-binding domain (residues 1 to 38)
is highly hydrophobic. The ATG start codon is located
204 nucleotides downstream of the trans-cription start
site (Wu et al., 1999). Similarly as other members of
the cytochrome P450 (CYP) enzyme superfamily,
CYP7B1 contains heme iron as a cofactor. Human
CYP7B1 shares 40% seq-uence identity with human
CYP7A1, the other member of the CYP7 family.
DNA/RNA
Description
The human CYP7B1 DNA maps to NM_004820
(Entrez-Gene) and spans a region of 202.66 kB.
CYP7B1 is located on chromosome 8 and consists of
six exons.
Expression
Expression of CYP7B1 is reported in many human
tissues including brain, kidney, liver, lung, heart,
prostate, testis, ovary, placenta, pancreas, intestine,
colon and thymus (Wu et al., 1999).
Transcription
The full length CYP7B1 mRNA is 2,395 bp with an
open reading rame of 1,521 bp.
Human CYP7B1 gene structure. Exons are represented by red bars with exon numbers at the bottom.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
275
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1)
Norlin M
study comparing allele frequency in an Oriental
(Korean) population and a Caucasian (Swedish)
population, the frequency of the uncommon G-allele
was found to be much lower in the Oriental population
(Jakobsson et al., 2004).
Localisation
Most reports indicated localization to the membrane of
the endoplasmic reticulum. There are some data
indicating possible CYP7B1-related activity also in
mitochondria but it is unclear whether this activity
represents CYP7B1 or another enzyme species
(Axelson et al., 1992; Pandak et al., 2002).
Implicated in
Function
Prostate cancer
CYP7B1 converts a number of steroids into their
7alpha-hydroxyderivatives (Toll et al., 1994; Rose et
al., 1997; Yau et al., 2006; Norlin and Wikvall, 2007).
In addition to 7alpha-hydroxylation, forma-tion of
6alpha, 6beta-, and 7beta-hydroxyderiva-tives also has
been reported for this enzyme. Some well-known
substrates for CYP7B1 are: 27-hydro-xycholesterol and
25-hydroxycholesterol
(choles-terol
derivatives);
dehydroepiandrosterone (DHEA) and pregnenolone
(sex hormone precursors and neurosteroids); 5alphaandrostane-3beta,17beta-diol
and
5-androstene3beta,17beta-diol (estrogen recap-tor ligands). The
catalytic reactions performed by CYP7B1 may lead to
elimination of the steroids from the cell and thereby
reduce the cellular levels of the substrates for this
enzyme. Also, several of the products formed by
CYP7B1 are reported to have physiological effects.
Thus, CYP7B1 may in some cases be part of
biosynthetic pathways to form active compounds.
Note
High expression of CYP7B1 protein is found in highgrade prostatic intraepithelial neoplasia (PIN) and
adenocarcinomas (Olsson et al., 2007). Local
methylation of the CYP7B1 promoter is suggested to
be important for regulation of CYP7B1 in human
prostate tissue. In addition, a functional C-G
polymorphism in the CYP7B1 promoter has been
associated with a different allele frequency in two
ethnic populations with great differences in the
incidence of prostate cancer (Swedes and Koreans)
(Jakobsson et al., 2004). A connection between
CYP7B1 and prostate cancer may be related to the
action of estrogen receptor beta (ERbeta), since
metabolism by CYP7B1 is reported to affect the levels
of ligands for ERbeta, which is believed to have antiproliferative effects (Weihua et al., 2002; Martin et al.,
2004). Sex hormones are important for growth of
prostate and other tissues, both during normal and
malignant conditions. A potential role for CYP7B1 in
tissue growth is supported by data indicating that the
Akt/PI3K (phosphoinositide 3-kinase) cascade, a
signalling pathway important for cellular growth,
affects the CYP7B1 gene (Tang et al., 2008). In human
prostate cancer LNCaP cells, CYP7B1 promoter
activity is affected by both androgens and estrogens,
suggesting important functions in hormonal signalling
(Tang and Norlin, 2006).
Homology
The CYP7B1 gene is conserved in chimpanzee, dog,
cow, mouse, rat, chicken, and zebrafish.
Mutations
Germinal
A homozygous mutation in the CYP7B1 gene (R388X)
was identified in an infant boy with defective bile acid
synthesis and severe cholestasis (Setchell et al., 1998).
The patient was the offspring of first cousins.
Mutations in the CYP7B1 gene (S363F, G57R, R417H,
F216S, R388X) have been associated with a form of
hereditary spastic paraplegia (HSP type 5)
characterized by motor neuron degeneration in affected
individuals of several families (Tsaousidou et al.,
2008). S363F and F216S was predicted to affect
phosphorylation of the mature protein. In addition,
studies on non-consanguineous cases of hereditary
spastic para-plegia indicate that a coding CYP7B1
polymor-phism (c.971G>A) is associated with a
phenotype of cerebellar signs believed to complicate a
primary HSP phenotype (Schule et al., 2009).
A functional polymorphism was reported in the human
CYP7B1 promoter consisting of a C-G change located 104 nucleotides from the trans-cription start site
(Jakobsson et al., 2004). The C-G alteration at -104
creates a putative C/EBPbeta binding site and was
shown to result in higher transcriptional activity. In a
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Spastic Paraplegia Type 5A
Note
Mutations in the coding region of the CYP7B1 gene
has been found in patients with spastic paraplegia type
5, an upper-motor-neuron degenerative disease which
affects lower limb movement and results in extremity
weakness and spasticity, sometimes accompanied by
additional symptoms. Hereditary spastic paraplegia
(HSP) is characterized by axonal degeneration of
neurons in the corticospinal tracts and dorsal columns.
Sequence alterations in CYP7B1, believed to affect the
functionality of the enzyme, have been associated with
a pure form of autosomal-recessive HSP in several
families (Tsaousidou et al., 2008). The association of
an abnormal CYP7B1 gene with this neurodegenerative condition suggest that the pathogenic basis for
this disease is related either to effects on cholesterol
homeostasis in the brain (i e on CYP7B1-mediated
control of the levels of 27-hydroxycholesterol) or to
effects on the metabolism of dehydroepiandrosterone
and other neurosteroids.
276
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1)
Norlin M
inflammation and progressive destruction of the joints.
Other tissues also may be affected. Studies in a mouse
model for collagen-induced arthritis indicate
correlation of increased CYP7B1 activity with disease
progression (Dulos et al., 2004). In humans, CYP7B1 is
found in synovial tissues (connective tissues
surrounding the joints) from patients with rheumatoid
arthritis and CYP7B1 levels are up-regulated by
proinflammatory cytokines in human synoviocytes
(Dulos et al., 2005). Chronic inflam-matory diseases
including rheumatoid arthritis are known to be
associated with changes in levels of several steroids. It
has been proposed that the CYP7B1-formed 7alphahydroxy-DHEA
might
counteract
the
immunosuppressive effects of gluco-corticoids, which
are used in treatment of rheuma-toid arthritis.
Congenital Bile Acid Defect Type 3
(CBAS3)
Note
A mutation in the CYP7B1 gene was linked to
defective bile acid production, cholestasis and liver
cirrhosis in an infant boy who died at the age of < 1
year due to complications following liver transplantation (Setchell et al., 1998). Other symptoms
included hepatosplenomegaly, jaundice and increased
bleeding. The pathological findings were consistent
with accumulation of hepatotoxic unsaturated
monohydroxy bile acids. The patient had 4,500 times
higher levels of 27-hydroxycholes-terol than normal
and liver samples showed no 27-hydroxycholesterol
7alpha-hydroxylase activity. Failure to detect CYP7A1mediated 7alpha-hydroxylase activity in this patient as
well as in other infants of the same age led the authors
to suggest that CYP7B1 may be more important for
bile acid synthesis in early life than in adulthood
(Setchell et al., 1998).
References
Axelson M, Shoda J, Sjövall J, Toll A, Wikvall K. Cholesterol is
converted to 7 alpha-hydroxy-3-oxo-4-cholestenoic acid in liver
mitochondria. Evidence for a mitochondrial sterol 7 alphahydroxylase. J Biol Chem. 1992 Jan 25;267(3):1701-4
Alzheimer's Disease
Toll A, Wikvall K, Sudjana-Sugiaman E, Kondo KH, Björkhem I.
7 alpha hydroxylation of 25-hydroxycholesterol in liver
microsomes. Evidence that the enzyme involved is different
from cholesterol 7 alpha-hydroxylase. Eur J Biochem. 1994
Sep 1;224(2):309-16
Note
Some patients with Alzheimer's disease, a progress-sive
neurodegenerative disease that strongly impairs
cognition and memory, are reported to have altered
levels of CYP7B1 expression and/or CYP7B1-formed
metabolites. Some studies indi-cate reduced brain
expression of CYP7B1 in Alzheimer's disease (Yau et
al., 2003) whereas others report increased CYP7B1formed metabo-lites in serum from patients with this
disease (Attal-Khemis et al., 1998). The potential
role(s) of CYP7B1 in connection with Alzheimer's
disease remains unclear. Alzheimer's disease is
associated with build-up of neuritic plaques and
neurofibrillary tangles and progressive loss of neurons
and synapses in several parts of the brain. The etiology
of Alzheimer's disease is not well understood and the
underlying mechanisms are most likely complex. It has
been suggested that disturbed metabolism of
neurosteroids and/or other brain lipids may be one of
the contributing factors (Yau et al., 2003; Bjorkhem et
al., 2006). In some types of brain cells, CYP7B1dependent hydroxylation is the main metabolic fate for
neurosteroids
dehydro-epiandrosterone
and
pregnenolone. Also, the levels of CYP7B1 are higher in
the hippocampus than in other parts of the brain,
supporting a potential role for this enzyme related to
memory and cognition (Yau et al., 2003).
Rose KA, Stapleton G, Dott K, Kieny MP, Best R, Schwarz M,
Russell DW, Björkhem I, Seckl J, Lathe R. Cyp7b, a novel
brain cytochrome P450, catalyzes the synthesis of
neurosteroids 7alpha-hydroxy dehydroepiandrosterone and
7alpha-hydroxy pregnenolone. Proc Natl Acad Sci U S A. 1997
May 13;94(10):4925-30
Attal-Khémis S, Dalmeyda V, Michot JL, Roudier M, Morfin R.
Increased total 7 alpha-hydroxy-dehydroepiandrosterone in
serum of patients with Alzheimer's disease. J Gerontol A Biol
Sci Med Sci. 1998 Mar;53(2):B125-32
Setchell KD, Schwarz M, O'Connell NC, Lund EG, Davis DL,
Lathe R, Thompson HR, Weslie Tyson R, Sokol RJ, Russell
DW. Identification of a new inborn error in bile acid synthesis:
mutation of the oxysterol 7alpha-hydroxylase gene causes
severe neonatal liver disease. J Clin Invest. 1998 Nov
1;102(9):1690-703
Wu Z, Martin KO, Javitt NB, Chiang JY. Structure and
functions of human oxysterol 7alpha-hydroxylase cDNAs and
gene CYP7B1. J Lipid Res. 1999 Dec;40(12):2195-203
Pandak WM, Hylemon PB, Ren S, Marques D, Gil G, Redford
K, Mallonee D, Vlahcevic ZR. Regulation of oxysterol 7alphahydroxylase (CYP7B1) in primary cultures of rat hepatocytes.
Hepatology. 2002 Jun;35(6):1400-8
Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine
pathway in the prostate, ERbeta, AR, 5alpha-androstane3beta,17beta-diol, and CYP7B1, regulates prostate growth.
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13589-94
Rheumatoid Arthritis and Inflammation
Note
Increased production of the CYP7B1-formed
metabolite 7alpha-hydroxy-DHEA has been suggested
to contribute to the chronic inflammation observed in
patients with rheumatoid arthritis (Dulos et al., 2005).
Rheumatoid arthritis is a chronic inflammatory disorder
with unclear etiology characterized by joint
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Yau JL, Rasmuson S, Andrew R, Graham M, Noble J, Olsson
T, Fuchs E, Lathe R, Seckl JR. Dehydroepiandrosterone 7hydroxylase CYP7B: predominant expression in primate
hippocampus and reduced expression in Alzheimer's disease.
Neuroscience. 2003;121(2):307-14
Dulos J, Verbraak E, Bagchus WM, Boots AM, Kaptein A.
Severity of murine collagen-induced arthritis correlates with
increased
CYP7B
activity:
enhancement
of
277
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1)
dehydroepiandrosterone metabolism by
Arthritis Rheum. 2004 Oct;50(10):3346-53
Norlin M
interleukin-1beta.
Norlin M, Wikvall K. Enzymes in the conversion of cholesterol
into bile acids. Curr Mol Med. 2007 Mar;7(2):199-218
Jakobsson J, Karypidis H, Johansson JE, Roh HK, Rane A,
Ekström L. A functional C-G polymorphism in the CYP7B1
promoter region and its different distribution in Orientals and
Caucasians. Pharmacogenomics J. 2004;4(4):245-50
Olsson M, Gustafsson O, Skogastierna C, Tolf A, Rietz BD,
Morfin R, Rane A, Ekström L. Regulation and expression of
human CYP7B1 in prostate: overexpression of CYP7B1 during
progression of prostatic adenocarcinoma. Prostate. 2007 Sep
15;67(13):1439-46
Martin C, Ross M, Chapman KE, Andrew R, Bollina P, Seckl
JR, Habib FK. CYP7B generates a selective estrogen receptor
beta agonist in human prostate. J Clin Endocrinol Metab. 2004
Jun;89(6):2928-35
Tang W, Pettersson H, Norlin M. Involvement of the PI3K/Akt
pathway in estrogen-mediated regulation of human CYP7B1:
identification of CYP7B1 as a novel target for PI3K/Akt and
MAPK signalling. J Steroid Biochem Mol Biol. 2008 Nov;112(13):63-73
Dulos J, van der Vleuten MA, Kavelaars A, Heijnen CJ, Boots
AM. CYP7B expression and activity in fibroblast-like
synoviocytes from patients with rheumatoid arthritis: regulation
by proinflammatory cytokines. Arthritis Rheum. 2005
Mar;52(3):770-8
Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA,
Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton
MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence
alterations within CYP7B1 implicate defective cholesterol
homeostasis in motor-neuron degeneration. Am J Hum Genet.
2008 Feb;82(2):510-5
Björkhem I, Heverin M, Leoni V, Meaney S, Diczfalusy U.
Oxysterols and Alzheimer's disease. Acta Neurol Scand Suppl.
2006;185:43-9
Schüle R, Brandt E, Karle KN, Tsaousidou M, Klebe S, Klimpe
S, Auer-Grumbach M, Crosby AH, Hübner CA, Schöls L,
Deufel T, Beetz C. Analysis of CYP7B1 in nonconsanguineous cases of hereditary spastic paraplegia.
Neurogenetics. 2009 Apr;10(2):97-104
Tang W, Norlin M. Regulation of steroid hydroxylase CYP7B1
by androgens and estrogens in prostate cancer LNCaP cells.
Biochem Biophys Res Commun. 2006 Jun 2;344(2):540-6
Yau JL, Noble J, Graham M, Seckl JR. Central administration
of
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cytochrome
P450-7B
product
7
alphahydroxypregnenolone improves spatial memory retention in
cognitively impaired aged rats. J Neurosci. 2006 Oct
25;26(43):11034-40
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
This article should be referenced as such:
Norlin M. CYP7B1 (cytochrome P450, family 7, subfamily B,
polypeptide 1). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):275-278.
278
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
EPHA3 (EPH receptor A3)
Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd
Leukaemia Foundation Research Laboratory, Queensland Institute of Medical Research, 300 Herston Road,
Brisbane Queensland 4006, Australia (BS, BD, JM, AB); Department of Biochemistry and Molecular
Biology, PO Box 13D, Monash University, Clayton Victoria 3800, Australia (ML); Department of Medicine,
University of Queensland, St Lucia Queensland 4067, Australia (AB)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/EPHA3ID40463ch3p11.html
DOI: 10.4267/2042/44710
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: EC 2.7.10.1; ETK; ETK1; EphA3;
HEK; HEK4; TYRO4
HGNC (Hugo): EPHA3
Location: 3p11.2
Local order: (tel) C3orf38 (ENSG00000179021) ->,
949,562bp, EPHA3 (374,609bp) ->, 720,071bp, <AC139337.5 (ENSG00000189002) (cen)
Note
EPHA3 is flanked by two gene deserts.
Note
EPHA3 spans the human tile path clones CTD2532M17, RP11-784B9 and RP11-547K2.
Description
EPHA3 consists of 17 exons and 16 introns and spans
375kb of genomic DNA. It is the second largest of the
EPH genes after EPHA6.
Figure 1: Chromosomal location of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)).
Figure 2: Genomic neighbourhood of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
279
EPHA3 (EPH receptor A3)
Stringer B, et al.
Figure 3: Genomic organisation of EPHA3.
present in sponges, worms and fruit flies. The
expansion in the number of Eph receptor-encoding
genes along with genes encoding their ligands, the
ephrins (Eph receptor interacting proteins), is proposed
to have contributed to the increase in complexity of the
bilaterian body plan. Genes encoding EphA3 are found
in the genomes of representative members of at least
five of the seven classes of vertebrates including bony
fish (zebrafish, pufferfish, medaka), amphibians
(African clawed frog), reptiles (green anole lizard),
birds (chicken) and mammals (platypus, possum,
human).
Fourteen Eph receptors have been identified in
vertebrates. These are subdivided into either EphA
(EphA1, EphA2, EphA3, EphA4, EphA5, EphA6,
EphA7, EphA8, EphA10) or EphB (EphB1, EphB2,
EphB3, EphB4, EphB6) subclasses which differ
primarily in the structure of their ligand binding
domains. EphA receptors also exhibit greater affinity
for binding GPI-linked ephrin-A ligands while EphB
receptors bind transmembrane ephrin-B ligands. While
interactions are somewhat promis-cuous, and some
cross-class binding occurs, each Eph receptor displays
distinct affinity for the different ephrin ligands. The
high affinity ligands for EphA3 are ephrin-A2 and
ephrin-A5. EphA3 also binds ephrin-A3 and ephrin-A4
with lower affinity.
Eph-ephrin binding involves contact between cells.
Upon
binding,
receptor-ligand
dimers
form
heterotetramers, which further assemble into higher
order signalling clusters. Several moieties in the EphA3
receptor extracellular region mediate ephrin binding. A
high-affinity binding site in the N-terminal ephrin
binding domain mediates inter-cellular Eph-ephrin
interaction. Two additional lower-affinity ephrinbinding sites, one in the ephrin-binding domain and the
other in the cysteine-rich region, are involved in
clustering of Eph-ephrin complexes.
Following ephrin-A5-mediated EphA3 receptor
clustering, intracellular signalling by EphA3 receptors
is initiated by autophosphorylation of three defined
tyrosine residues, two in the highly conserved
juxtamembrane region and the third in the activation
loop of the kinase domain (Y779). Rapid reorganisation
of the actin and myosin cytoskeleton follows, leading
to retraction of cellular protrusions, membrane
blebbing and cell detachment, following association of
the adaptor protein CrkII with tyrosine phosphorylated
EphA3 and activation of RhoA signalling.
Such Eph-ephrin interaction triggers bidirectional
signalling, that is signalling events within both Ephand ephrin-bearing cells, an unusual phenomenon for
receptor tyrosine kinases, most of which interact with
soluble ligands. Subsequently, depending on the
cellular context (including the identity of the
interacting Eph-ephrin receptor-ligand pairs, their
relative levels on interacting cells, the presence of
additional Ephs and ephrins and their alternative
Transcription
Two alternatively spliced transcript variants have been
described (NM_005233.5, a 5,807 nucleotide mRNA
and NM_182644.2, a 2,684 nucleotide mRNA). The
shorter transcript results in truncation within the
extracellular domain of EphA3 and is predicted to
produce a soluble protein. The 5' end of EPHA3 is
associated with a CpG island, a feature common to all
EPH genes. The EPHA3 promoter also lacks a TATA
box and transcription initiates from multiple start sites.
Pseudogene
None identified.
Protein
Note
The Eph receptors constitute the largest of the 20
subfamilies of human receptor tyrosine kinases. The
founding member of this group was isolated originally
from an erythropoietin producing hepato-ma cell line.
Figure 4: Domain organisation of EphA3.
Description
The EPHA3 gene encodes a 983 amino acid protein
with a calculated molecular weight of 110.1kDa and an
isoelectric point of 6.7302. Amino acids 1-20 constitute
a signal peptide. The predicted mole-cular mass of the
translated protein minus the signal peptide is 92.8kDa.
The 521 amino acid extra-cellular domain contains five
potential sites for N-glycosylation such that EphA3 is
typically detected as a 135kDa glycoprotein. This
mature isoform of EphA3 is a single-pass
transmembrane receptor tyrosine kinase. At its Nterminus is a 174 amino acid ligand binding domain, a
14 amino acid EGF-like domain and two membrane
proximal fibro-nectin type III repeats. Amino acids 21376 of the extracellular domain also are rich in cysteine
residues. The intracellular domain contains the tyrosine
kinase domain and a sterile alpha motif. EphA3 lacks a
PDZ domain interacting motif present in EphA7,
EphB2, EphB3, EphB5 and EphB6. Activation of the
EphA3 receptor tyrosine kinase domain is associated
with two tyrosine residues in the juxtamembrane region
(Y596, Y602) that are sites of autophosphorylation and
interact with the kinase domain to modulate its activity.
EphA3 belongs to an evolutionarily ancient subfamily
of receptor tyrosine kinases with mem-bers being
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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EPHA3 (EPH receptor A3)
Stringer B, et al.
isoforms, and the net effect of interaction with
additional signalling pathways) this either results in
repulsion or promotes adhesion of the interacting cells.
Cellular repulsion and the termination of Eph-ephrin
signalling require disruption of the receptor-ligand
complex. This is brought about either by enzymatic
cleavage of the tethered ephrin ligand in cis or in trans
or by endocytosis of Eph-ephrin complexes. EphA3ephrin-A2 receptor-ligand complexes are shed from
ephrin-A2 bearing cells following receptor-ligand
binding when ADAM10 (a disintegrin and
metalloprotease 10), associated with ephrin-A2, cleaves
ephrin-A2. Conversely, intercellular EphA3-ephrin-A5
receptor-ligand complexes are broken when EphA3associated ADAM10 cleaves ephrin-A5 on opposing
cells, following binding to EphA3. The post-cleavage
ephrin-A5-EphA3 complex is then endocytosed by the
EphA3-expressing cell.
While cellular repulsion is often the outcome of Ephephrin interaction, in some circumstances adhesion
may persist. For example, ADAM10 has been observed
not to cleave ephrin-A5 following EphA3-ephrin-A5
interaction involving LK63 cells in which high
intracellular protein tyrosine phosphatase activity also
appears
to
counter
ephrin-A5
stimulated
phosphorylation of EphA3, holding the receptor in an
inactive, unphosphorylated state. Also cis interaction
between EphA3 and ephrin-A2 expressed on the same
cell surface has been reported to block EphA3
activation by ephrins acting in trans, the cis interaction
site being independent of the ligand binding domain.
Another mechanism that may favour stable cell-cell
adhesion involves truncated Eph receptor isoforms
acting in a dominant negative manner. While activation
of full length EphA7 by ephrin-A5 results in cellular
repulsion, ephrin-A5-induced phosphorylation of
EphA7 is inhibited by two EphA7 splice variants with
truncated kinase domains and adhesion results. A splice
variant of EPHA3 also has been reported and is
predicted to give rise to a soluble isoform of EphA3.
Whether this soluble variant of EphA3, which is
truncated before the transmembrane domain, functions
in a similar manner to the shorter EphA7 isoforms has
not been established.
While important details of EphA3 signalling have been
determined, more complete understanding of EphA3
activity will require knowledge of the full complement
of EphA3 interacting proteins. Substrates that are
targets for the tyrosine kinase activity of EphA3 have
yet to be defined and potential mediators or modulators
of EphA3 signalling output such as Src family kinases,
additional phosphotyrosine binding adaptors, SAM
domain interacting factors, interaction with other
receptor kinases and crosstalk with other signalling
pathways, and the regulatory role of phosphatases all
remain to be explored. Based on the range of
interacting proteins identified for other Eph receptors
(some common to more than one Eph, others
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
apparently unique to individual Ephs) additional
effectors of EphA3 signalling output are likely.
Expression
EphA3 was first identified as an antigen expressed at
high levels (10,000-20,000 copies per cell) on the
surface of the LK63 pre-B cell acute lymphoblastic
leukaemia cell line. It also was found to be expressed
by JM, HSB-2 and MOLT-4 T-cell leukaemic cell
lines, in CD28-stimulated Jurkat cells, and in 16 of 42
cases of primary T-cell lymphoma (but not normal
peripheral T lymphocytes nor in any subset of thymusderived developing T cells), as well as at low frequency
in acute myeloid leukaemia and chronic lymphocytic
leukaemia EphA3 is not expressed by many other
haematopoietic cell lines.
Subsequently, EphA3 expression has been shown to be
most abundant, and also highly regulated both
temporally
and
spatially,
during
vertebrate
development. Prominent EphA3 expression occurs in
the neural system, including the retinal ganglion cells
of the embryonic retina in a graded distribution from
anterior/nasal (lowest) to posterior /temporal (highest);
the cerebrum, thalamus, striatum, olfactory bulb,
anterior commissure, and corpus callosum of the
forebrain; and the medial motor column ventral motor
neurons of the spinal cord; and extraneurally by
mesodermally-derived tissues including the paraxial
musculature, tongue musculature, submucosa of the
soft palate, capsule of the submandibular gland, cortical
rim of bone, thymic septae, media of the pharynx,
trachea, great vessels, small intestine and portal vein,
cardiac valves, and the renal medulla. In adult tissues
EphA3 expression is more restricted and detected at
significantly lower levels than during early
development.
Localisation
Isoform 1: Cell membrane; single-pass type I
membrane protein.
Isoform 2: Secreted.
Function
Eph receptors modulate cell shape and movement
through reorganisation of the cytoskeleton and changes
in cell-cell and cell-substrate adhesion, and are
involved in many cellular migration, sorting (tissue
patterning) and guidance events, most often during
development, and in particular involving the nervous
system. There is evidence too that Eph receptor
signalling influences cell proliferation and cell-fate
determination and growing recognition that Eph
receptors function in adult tissue homeostasis.
EphA3 is thought to play a role in retinotectal mapping,
the tightly patterned projection of retinal ganglion cell
axons from the retina to the optic tectum (or superior
colliculus in mammals). In chicks, posterior retinal
ganglion axons expressing highest levels of EphA3
project to the anterior tectum where the graded
281
EPHA3 (EPH receptor A3)
Stringer B, et al.
expression of ephrin-A2 and ephrin-A5 is lowest and
are excluded from projecting more posteriorly where
ephrin-A2/A5 expression is highest. More direct
evidence of non-redundant function for EphA3 has
come from phenotypic analysis of EphA3 knockout
mice. Approximately 70-75% of EphA3 null mice die
within 48 hours of birth with post-mortem evidence of
pulmonary oedema secondary to cardiac failure. These
mice exhibit hypoplastic atrioventricular endocardial
cushions and subsequent atri-oventricular valve and
atrial membranous septal defects, with endocardial
cushion explants from these mice giving rise to fewer
migrating cells arising from epithelial to mesenchymal
trans-formation. Expression of EphA3 in the spinal
cord appears to be redundant as axial muscle targeting
by medial motor column motor axons and the
organisation of the motor neuron columns is not
altered. EphA4 is the only other EphA receptor also
expressed by developing spinal cord motor neurons and
in mice lacking EphA3 and EphA4 these receptors
together repel axial motor axons from neighbouring
ephrin-A-expressing
sensory
axons,
inhibiting
intermingling of motor and sensory axons and
preventing mis-projection of motor axons into the
dorsal root ganglia. In contrast to the chick, EphA3 is
not expressed by mouse retinal ganglion cells. Instead
the closely related receptors EphA5 and EphA6 (see
homology below) are expressed in a low nasal to high
temporal gradient. However, if EphA3 is ectopically
expressed in retinal ganglion cells in mice these axons
project to more rostral positions in the superior
colliculus.
A function for soluble EphA3 has not been reported
although potentially this isoform might play a role in
promoting cell adhesion (see above) or act as a tumour
suppressor protein (see below).
(NP_005224),
EphA4
(NP_004429),
EphA5
(NM_004439), EphA6 (ENSP00000374323), EphA7
(NP_004431),
EphA8
(NP_065387),
EphA10
(NP_001092909), EphB1 (NP_004432), EphB2
(NP_004433),
EphB3
(NP_004434),
EphB4
(NP_004435) and EphB6 (NP_004436).
Homology
Somatic
Phylogenetic tree for the Eph receptors. Amino acid
sequences used for this compilation were EphA1
(NP_005223), EphA2 (NM_004431), EphA3
Somatic mutations in EPHA3 have been detected in
lung adenocarcinoma (T166N, G187R, S229Y,
W250R, M269I, N379K, T393K, A435S, D446Y,
Mutations
Note
Seven nonsynonymous single nucleotide polymerphisms (all missense) are recorded in the dbSNP
database for EPHA3. Recognised allelic variation
occurs for the following EphA3 amino acids: I564V
(rs56081642),
C568S
(rs56077781),
L590P
(rs56081642),
T608A
(rs17855794),
G777A
(rs34437982), W924R (rs35124509) and H914R
(rs17801309).
Germinal
To date no germinal mutations in EPHA3 have been
associated with disease.
Figure 6: Sites of somatic mutations in EphA3 identified in lung adenocarcinoma colorectal carcinoma, glioblastoma multiforme and
metastatic melanoma.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
282
EPHA3 (EPH receptor A3)
Stringer B, et al.
S449F, G518L, T660K, D678E, R728L, K761N,
G766E, T933M), colorectal carcinoma (T37K, N85S,
I621L, S792P, D806N), glioblastoma multi-forme
(K500N, A971P) and metastatic melanoma (G228R).
References
Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F. A novel
putative tyrosine kinase receptor encoded by the eph gene.
Science. 1987 Dec 18;238(4834):1717-20
Implicated in
Boyd AW, Ward LD, Wicks IP, Simpson RJ, Salvaris E, Wilks
A, Welch K, Loudovaris M, Rockman S, Busmanis I. Isolation
and characterization of a novel receptor-type protein tyrosine
kinase (hek) from a human pre-B cell line. J Biol Chem. 1992
Feb 15;267(5):3262-7
Prostate cancer
Note
EPHA3 was among the genes whose expression was
upregulated during androgen-independent progresssion
in an LNCaP in vitro cell model of prostate cancer.
Wicks IP, Wilkinson D, Salvaris E, Boyd AW. Molecular cloning
of HEK, the gene encoding a receptor tyrosine kinase
expressed by human lymphoid tumor cell lines. Proc Natl Acad
Sci U S A. 1992 Mar 1;89(5):1611-5
Melanoma
Kilpatrick TJ, Brown A, Lai C, Gassmann M, Goulding M,
Lemke G. Expression of the Tyro4/Mek4/Cek4 gene
specifically marks a subset of embryonic motor neurons and
their muscle targets. Mol Cell Neurosci. 1996 Jan;7(1):62-74
Note
A melanoma patient with an especially favourable
evolution of disease, associated with a very strong and
sustained anti-tumour cytotoxic T lymphocyte
response, was found to have a lytic CD4 clone that
recognised an EphA3 antigen presented by the HLA
class II molecule HLA- DRB1*1101. 94% (75 of 80) of
melanomas examined expressed EphA3 in contrast to
normal melanocytes which do not express detectable
EphA3.
Lackmann M, Mann RJ, Kravets L, Smith FM, Bucci TA,
Maxwell KF, Howlett GJ, Olsson JE, Vanden Bos T, Cerretti
DP, Boyd AW. Ligand for EPH-related kinase (LERK) 7 is the
preferred high affinity ligand for the HEK receptor. J Biol Chem.
1997 Jun 27;272(26):16521-30
Hock B, Böhme B, Karn T, Yamamoto T, Kaibuchi K, Holtrich
U, Holland S, Pawson T, Rübsamen-Waigmann H, Strebhardt
K. PDZ-domain-mediated interaction of the Eph-related
receptor tyrosine kinase EphB3 and the ras-binding protein
AF6 depends on the kinase activity of the receptor. Proc Natl
Acad Sci U S A. 1998 Aug 18;95(17):9779-84
Lung cancer, Sarcoma, and Renal cell
carcinoma
Lackmann M, Oates AC, Dottori M, Smith FM, Do C, Power M,
Kravets L, Boyd AW. Distinct subdomains of the EphA3
receptor mediate ligand binding and receptor dimerization. J
Biol Chem. 1998 Aug 7;273(32):20228-37
Note
44% (11 of 25) of small cell lung cancer, 24% (10 of
41) of non-small cell lung cancer, 58% (17 of 29) of
sarcomas, and 31% (12 of 38) of renal cell carcinomas
expressed EphA3 at levels significantly higher than the
corresponding normal tissues.
Dottori M, Down M, Hüttmann A, Fitzpatrick DR, Boyd AW.
Cloning and characterization of EphA3 (Hek) gene promoter:
DNA methylation regulates expression in hematopoietic tumor
cells. Blood. 1999 Oct 1;94(7):2477-86
Breakpoints
Brown A, Yates PA, Burrola P, Ortuño D, Vaidya A, Jessell
TM, Pfaff SL, O'Leary DD, Lemke G. Topographic mapping
from the retina to the midbrain is controlled by relative but not
absolute levels of EphA receptor signaling. Cell. 2000 Jul
7;102(1):77-88
Note
No reported breakpoints identified to date nor
recognised fusion proteins involving EphA3.
Castresana J. Selection of conserved blocks from multiple
alignments for their use in phylogenetic analysis. Mol Biol Evol.
2000 Apr;17(4):540-52
To be noted
Note
Soluble forms of EphA3 appear to inhibit tumour
angiogenesis and tumour progression suggesting that
specific inhibition by soluble EphA3 may be
therapeutically useful.
The IIIA4 monoclonal antibody originally raised
against LK63 human acute pre-B leukemia cells and
used to affinity isolate EphA3 binds the native EphA3
globular ephrin-binding domain with sub-nanomolar
affinity (KD ~5x10-10 mol/L). Like ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation,
contraction of the cytoskeleton, and cell rounding.
Moreover, radio-metal conju-gates of ephrin-A5 and
IIIA4 retain their EphA3-binding affinity, and in mouse
xenografts localise to, and are internalised rapidly into
EphA3-positive, human tumours.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Chiari R, Hames G, Stroobant V, Texier C, Maillère B, Boon T,
Coulie PG. Identification of a tumor-specific shared antigen
derived from an Eph receptor and presented to CD4 T cells on
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contact-mediated axon repellent. Science. 2000 Aug
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Nature.
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towards dynamic graphics and annotations for analyses of
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Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T,
Dietmaier W, Landthaler M, Vogt T. Differential gene
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tissues and cancers. Clin Chem. 2004 Mar;50(3):490-9
Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD,
Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S,
Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J,
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Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S,
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Stringer B, et al.
Patterns of somatic mutation in human cancer genomes.
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(EPH receptor A3). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(3):279-285.
285
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
JAZF1 (JAZF zinc finger 1)
Hui Li, Jeffrey Sklar
University of Virginia Medical School, Charlottesville, VA 22908, USA (HL), Department of Pathology,
Yale University, New haven, CT, USA (HL, JS)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/JAZF1ID41036ch7p15.html
DOI: 10.4267/2042/44711
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Expression
Other names: TIP27; ZNF802; DKFZp761K2222
HGNC (Hugo): JAZF1
Location: 7p15.2
Expressed in all the tissues tested with variable level.
The tissues or organs that express JAZF1 include
cerebellum,
lung,
thymus,
liver,
kidney,
stomach/esophagus, skeleton muscle, skin and eye.
Localisation
Mostly nucleus.
Function
Description
JAZF1 has three C2H2-type zinc fingers. It is mostly
detected within the nucleus, with lesser amounts found
in the cytoplasm. JAZF1 copurifies with chromatin,
and presumably has DNA-binding properties. It has
been reported to interact with TAK1 and function as a
transcriptional repressor of the TAK1 gene.
SNPs in intron 1 of JAZF1 has been reported to be
associated with type 2 diabetes and body height.
SNPs in intron 2 of JAZF1 have been reported to be
associated with reduced prevalence of prostate cancer.
Chimeric JAZF1-JJAZ1 protein (amino acid sequence
of the first three exons of JAZF1 joined to sequence of
the last 15 exons of JJAZ1) resulting from transsplicing of precursor mRNAs and identical to a product
generated from the JAZF1-JJAZ1 gene fusion in
endometrial tumors has been found in normal
endometrium.
5 exons; spans 350kb.
Homology
Transcription
Unkown.
Major transcript: 2,980bp; coding sequence: 52-783.
Mutations
Metaphase FISH using as probe YAC908B12,
encompasses the entire JAZF1 at 7p15.2.
which
DNA/RNA
Protein
Somatic
Description
JAZF1 has been identified at the breakpoints of a
recurrent chromosomal translocation, the
243 amino acids.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
286
JAZF1 (JAZF zinc finger 1)
Li H, Sklar J
t(7;17)(p15;q21), in endometrial stromal tumors
(benign nodules and sarcomas). The translocation leads
to a JAZF1-JJAZ1 fusion gene. This gene fusion is
detected in about 50% of endometrial stromal sarcomas
and most endometrial stromal nodules.
Another common chromosomal translocation in
endometrial stroma sarcomas, the t(6;7)(p21;p15),
results in a JAZF1-PHF1 fusion. About 25-30% of
endometrial stromal sarcomas are reported to contain
this fusion. The sites of fusion within JAZF1 RNA to
JJAZ1 and PHF1 RNA sequence are the same. Both
JJAZ1(also called SUZ12) and PHF1 belong to the
Polycomb group (PcG) gene family.
Breakpoints
Implicated in
t(7;17)(p15;q21) / endometrial stromal
nodule and endometrial sarcoma
Disease
Endometrial stroma nodule and sarcoma.
Cytogenetics
t(7;17)(p15;q21)
Hybrid/Mutated gene
JAZF1-JJAZ1
Abnormal protein
JAZF1-JJAZ1
Oncogenesis
The fusion protein protects cells from hypoxia-induced
apoptosis, and also promotes proliferation when the
wild-type allele of JJAZ1 is silenced (as it is in
endometrial
stromal
sarcomas
carrying
the
t(7;17)(p15;q21)).
References
Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den
Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of
the JAZF1 and JJAZ1 genes in endometrial stromal tumors.
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53
Micci F, Panagopoulos I, Bjerkehagen B, Heim S. Consistent
rearrangement of chromosomal band 6p21 with generation of
fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial
stromal sarcoma. Cancer Res. 2006 Jan 1;66(1):107-12
Li H, Ma X, Wang J, Koontz J, Nucci M, Sklar J. Effects of
rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell
proliferation and survival. Proc Natl Acad Sci U S A. 2007 Dec
11;104(50):20001-6
Nucci MR, Harburger D, Koontz J, Dal Cin P, Sklar J.
Molecular analysis of the JAZF1-JJAZ1 gene fusion by RTPCR and fluorescence in situ hybridization in endometrial
stromal neoplasms. Am J Surg Pathol. 2007 Jan;31(1):65-70
t(6;7)(p21;p15)/ endometrial stroma
sarcoma
Disease
Endometrial stroma sarcoma.
Cytogenetics
t(6;7)(p21;p15)
Hybrid/Mutated gene
JAZF1-PHF1
Abnormal protein
JAZF1-PHF1
Oncogenesis
The function of the JAZF1-PHF1 fusion is not
currently known.
Frayling TM, Colhoun H, Florez JC. A genetic link between
type 2 diabetes and prostate cancer. Diabetologia. 2008
Oct;51(10):1757-60
Frayling TM, Colhoun H, Florez JC. A genetic link between
type 2 diabetes and prostate cancer. Diabetologia. 2008
Oct;51(10):1757-60
Li H, Wang J, Mor G, Sklar J. A neoplastic gene fusion mimics
trans-splicing of RNAs in normal human cells. Science. 2008
Sep 5;321(5894):1357-61
Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr
N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A,
Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J,
Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ,
Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher
FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole
GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr,
Hoover R, Hayes RB, Hunter DJ, Chanock SJ. Multiple loci
identified in a genome-wide association study of prostate
cancer. Nat Genet. 2008 Mar;40(3):310-5
Prostate carcinoma
Oncogenesis
A SNIP in intron 2 of JAZF1 is associated with a
somewhat decreased risk of prostate cancer, especially
cancers that have been classified as being less
aggressive. The mechanism by which polymer-phisms
alter the susceptibility toward prostate cancer is not
currently known.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T,
de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K,
Boström KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K,
Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ,
Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM,
287
JAZF1 (JAZF zinc finger 1)
Li H, Sklar J
Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ,
Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE,
Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K,
Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T,
Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C,
Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N,
Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR,
Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW,
Rees M, Roix JJ, Sandbaek A, Shields B, Sjögren M,
Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G,
Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker
M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu
FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ,
Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI,
Boehnke M, Altshuler D. Meta-analysis of genome-wide
association data and large-scale replication identifies additional
susceptibility loci for type 2 diabetes. Nat Genet. 2008
May;40(5):638-45
Johansson A, Marroni F, Hayward C, Franklin CS, Kirichenko
AV, Jonasson I, Hicks AA, Vitart V, Isaacs A, Axenovich T,
Campbell S, Dunlop MG, Floyd J, Hastie N, Hofman A, Knott
S, Kolcic I, Pichler I, Polasek O, Rivadeneira F, Tenesa A,
Uitterlinden AG, Wild SH, Zorkoltseva IV, Meitinger T, Wilson
JF, Rudan I, Campbell H, Pattaro C, Pramstaller P, Oostra BA,
Wright AF, van Duijn CM, Aulchenko YS, Gyllensten U.
Common variants in the JAZF1 gene associated with height
identified by linkage and genome-wide association analysis.
Hum Mol Genet. 2009 Jan 15;18(2):373-80
Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram
DO, Henderson BE, Haiman CA. Generalizability of
associations from prostate cancer genome-wide association
studies in multiple populations. Cancer Epidemiol Biomarkers
Prev. 2009 Apr;18(4):1285-9
This article should be referenced as such:
Li H, Sklar J. JAZF1 (JAZF zinc finger 1). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(3):286-288.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
288
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
LPAR1 (lysophosphatidic acid receptor 1)
Mandi M Murph, Harish Radhakrishna
University of Georgia College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, 250 W
Green Street, Rm 376 Athens, Georgia 30602 USA (MMM); Global Research & Technology, The CocaCola Company, 1 Coca-Cola Plaza Atlanta, GA 30313 USA (HR)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/LPAR1ID40405ch9q31.html
DOI: 10.4267/2042/44712
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: EDG2; GPR26; LPA-1;
Mrec1.3; VZG1; edg-2; rec.1.3; vzg-1
HGNC (Hugo): LPAR1
Location: 9q31.3
Protein
LPA1;
Description
LPAR1 is an abbreviation for the LPA1 receptor, the
first receptor cloned and identified from a growing
number of LPA receptors that includes the Edg-family
and the purinergic receptors.
DNA/RNA
Expression
LPAR1 is ubiquitously expressed throughout cells and
tissues in the body.
High level of expression is found in amygdale,
Note
mRNA length 3104 or 3182 bp, depending on
alternative splicing.
Figure of the LPAR1, a G protein-coupled receptor, spanning the plasma membrane seven times. The receptor has three numbered
extracellular and intracellular loops that are involved in signal transduction. Also shown are the amino terminus and carboxyl terminal tail.
Three regions of the carboxyl terminal tail have been shown to be important for the LPAR1 signaling and receptor regulation. LPAR1
contains a canonical Type 1 PDZ binding domain (a.a. 362-364) at the extreme C-terminus. This domain has been shown to be required
for LPA-induced cell proliferation and activation of Rho family GTPases via PDZ-Rho guanine nucleotide exchange factors. Further
upstream in the carboxyl terminal tail, LPAR1 contains a di-leucine sequence (a.a. 351 and 352), which is required for phorbol ester-
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
289
LPAR1 (lysophosphatidic acid receptor 1)
Murph MM, Radhakrishna H
induced internalization. Still further upstream lies a serine-rich cluster (a.a. 341-347) that is required for beta-arrestin association, which is
critical for signal attenuation and receptor endocytosis.
prefrontal cortex, caudate nucleus, hypothalamus,
medulla oblongata, olfactory bulb, parietal lobe, spinal
cord and thalamus.
Moderately high level of expression is found in
adipocytes, cingulated cortex, occipital lobe, pons,
whole brain, globus pallidus, subthalamic nucleus,
temporal lobe, appendix, monocytes and smooth
muscle.
Slightly above median level of expression is found in
bronchial epithelial cells, cerebellum peduncies, dorsal
root ganglia, ciliary ganglion, uterus, uterus corpus,
atrioventricular node, fetal lung, fetal thyroid, skeletal
muscle, cardiac myocytes, salivary gland, tongue and
lymph node. It is also expressed in tissues during
neuronal development. The expression of LPAR1 is
increased in blister skin compared to normal skin. The
mRNA of LPAR1 is significantly increased 8 days after
unilateral uretheral obstruction in mice kidneys where
expression is higher in the medulla than the cortex. The
expression of LPAR1 is variable in cancer.
mice have deficiencies in olfactory development that
impairs their ability to locate maternal nipples and
initiate suckling required for survival. The lack of
olfactant detection leads to 50% lethality among pups.
Other LPAR1-null mice demonstrate alterations in
neurotransmitters that mimic models of schizophrenia.
LPAR1-null mice are 10-15% shorter than wild-type
mice and have gross anatomical defects due to bone
development, including incisor overgrowth that affects
ability to feed. The LPAR1 functions in normal cortical
development and commits cortical neuroblasts to
differentiate through the neural lineage. It may also
play a role in the formation of dendritic spine synapses.
Through autotoxin-generated LPA, LPAR1 mediates
neuropathic pain induced by nerve injury. Activation of
the LPAR1 functions in the inflammatory response;
receptor activation stimulates the recruitment of
macrophages.
The LPAR1 positively regulates motility in a variety of
cell types, exerting a dominant signal in the absence of
LPAR4.
Localisation
Homology
It is a requirement of G protein-coupled receptor
functioning that receptors are embedded into
membranes for proper structure. The LPAR1 spans the
plasma membrane seven times in a barrel conformation
with three extracellular and three intracellular loops. At
steady state, LPAR1 is located on the plasma
membrane at the cell surface until it binds LPA, which
triggers
dynamin2-dependent,
clathrin-mediated
endocytosis into the cell. LPAR1 requires membrane
cholesterol for association with beta-arrestin, which
targets the receptor to clathrin-coated pits for
internalization. In addition to LPA, phorbol ester
stimulation of protein kinase C also induces
internalization of LPAR1, but this does not require
beta-arrestin.
Rather,
phorbol
ester-dependent
internalization of LPAR1 requires AP-2 clathrin
adaptors. The LPAR1 is subsequently sorted through
Rab-5 dependent early and recycling endosomes before
it is recycled back to the cell surface or degraded in
lysosomes.
The receptor may also be localized to the nuclear
membrane in the cell. Some evidence indicates that a
portion of the total cellular LPAR1 localizes to the
nuclear membrane in PC12 cells, micro-vascular
endothelial cells, and human bronchial epithelial cells.
The exact function of this nuclear LPAR1 pool is not
known.
The LPAR1 has significant homology with LPAR2
(57%) and LPAR3 (51%), members of the original or
classical endothelial differentiation gene (Edg) family.
It has approximately 33-38% homology with individual
sphingosine 1-phosphate receptors and no significant
homology with the purinergic family of receptors that
also bind LPA.
Mutations
Note
There are several single nucleotide polymorphisms
(SNPs) reported within the LPAR1 gene and several of
these are associated with altered phenotype and disease
states.
A functional SNP located in the promoter region of the
gene (-2,820G/A; rs10980705) is associated with
increased susceptibility to knee osteoarthritis in
Japanese by showing an increase in binding and
activity.
A change in amino acid sequence at position 125 from
glutamine to glutamate in the LPAR1 will result in the
ability of the receptor to recognize both S1P and LPA.
A change in amino acid sequence at position 236 from
threonine to lysine in the LPAR1 will result in the
enhanced activation of serum response factor.
Mutations in the LPAR1 were detected in a small
percentage of adenomas and adenocarcinomas of rats
given BHP in their drinking water. Missense mutations
in the LPAR1 were detected in rat hepatocellular
carcinomas induced by N-nitroso-diethylamine and
choline-deficient l-amino acid-defined diets.
Deletion of the PDZ domain of the receptor prevents
signal attenuation that controls LPA-mediated receptor
activation and cell proliferation.
Function
The LPAR1 binds LPA and initiates G proteindependent signal transduction cascades throughout the
cell that result in a number of functional outcomes,
depending on the specific cell or tissue type. The G
alpha proteins involved are Gi, Gq and G 12/13. The
receptor has critical functions that have been elucidated
through gene knock-out studies in mice. LPAR1-null
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
290
LPAR1 (lysophosphatidic acid receptor 1)
Murph MM, Radhakrishna H
LPAR1 links lung injury with pulmonary fibrosis
development.
Implicated in
References
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Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J.
Requirement for the lpA1 lysophosphatidic acid receptor gene
in normal suckling behavior. Proc Natl Acad Sci U S A. 2000
Nov 21;97(24):13384-9
Note
Overexpression of the LPAR1 in mice contributes to
the tumorigenicity and aggressiveness of ovarian
cancer.
Prognosis
Upregulation of the LPAR1 appears to enhance tumor
progression in the previous examples.
Oncogenesis
The LPAR1 is a proto-oncogene contributing to the
metastatic potential of breast cancers and may require
signals from ErbB2/HER2 dimerization. In a study
designed to assess the functional conseq-uences of
overexpression as it relates to breast carcinogenesis,
1000 selected/suspected cDNAs were inserted into
immortalized MCF-10A cells and a derivative cell line,
MCF-10A.B2 expressing an inducibly active variant of
ErbB2. The study examined three assays (cell
proliferation, migration and 3-D matrigel acinar
morphogenesis) and the LPAR1 scored positive in all
three; thus, it was determined to be a proto-oncogene in
this disease. Several observations are of interest: first,
the LPAR1 induced migration in the absence of ErbB2
activation but not in the absence of dimerization which
suggests that the LPAR1 may require weak signals
from ligand-independent dimerization of ErbB2 to
induce migration; second, in the acinar morphogenesis
assay, phenotypical changes of cells with the LPAR1
included the formation of features of invasive tumor
cells, such as disorganized acinar structure, large
structures and protrusive behavior; third, the LPAR1
was capable of establishing abnormal 3-D
morphogenesis in the absence of conditions to dimerize
ErbB2.
Wang DA, Lorincz Z, Bautista DL, Liliom K, Tigyi G, Parrill AL.
A single amino acid determines lysophospholipid specificity of
the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth
factor receptors. J Biol Chem. 2001 Dec 28;276(52):49213-20
Gobeil F Jr, Bernier SG, Vazquez-Tello A, Brault S,
Beauchamp MH, Quiniou C, Marrache AM, Checchin D,
Sennlaub F, Hou X, Nader M, Bkaily G, Ribeiro-da-Silva A,
Goetzl EJ, Chemtob S. Modulation of pro-inflammatory gene
expression by nuclear lysophosphatidic acid receptor type-1. J
Biol Chem. 2003 Oct 3;278(40):38875-83
Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE,
Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C,
Hemmati P, Hervieu G, Howarth A, Hughes ZA, Hunter AJ,
Latcham J, Pickering S, Pugh P, Rogers DC, Shilliam CS,
Maycox PR. LPA1 receptor-deficient mice have phenotypic
changes observed in psychiatric disease. Mol Cell Neurosci.
2003 Dec;24(4):1170-9
Murph MM, Scaccia LA, Volpicelli LA, Radhakrishna H.
Agonist-induced endocytosis of lysophosphatidic acid-coupled
LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent
pathway. J Cell Sci. 2003 May 15;116(Pt 10):1969-80
Avendaño-Vázquez SE, García-Caballero A, García-Sáinz JA.
Phosphorylation and desensitization of the lysophosphatidic
acid receptor LPA1. Biochem J. 2005 Feb 1;385(Pt 3):677-84
Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C,
Maycox PR, Dawson LA. Neurochemical changes in LPA1
receptor deficient mice--a putative model of schizophrenia.
Neurochem Res. 2005 Mar;30(3):371-7
Yamada T, Ohoka Y, Kogo M, Inagaki S. Physical and
functional interactions of the lysophosphatidic acid receptors
with PDZ domain-containing Rho guanine nucleotide exchange
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Pilpel Y, Segal M. The role of LPA1 in formation of synapses
among cultured hippocampal neurons. J Neurochem. 2006
Jun;97(5):1379-92
Lung injury
Note
The LPAR1 mediates fibroblast migration and
recruitment in the injured lung. The chemotactic
activity of fibroblasts is dependent on LPAR1
expression.
Disease
Pulmonary fibrosis
The concentration of LPA is elevated in bronchoalveolar lavage samples from patients with idio-pathic
pulmonary fibrosis. The fibroblasts of these patients
require expression of LPAR1 for the chemotactic
activity present in this pathology. Data suggests that
LPAR1-null mice are substantially protected from
fibroblast accumulation. This corresponds to lung
injury where aberrant wound-healing responses
exacerbate pulmonary fibrosis pathogenesis.
Prognosis
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Natarajan V, Pyne S, Pyne NJ. Integrin signalling regulates the
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receptor-1 (LPA1) in mammalian cells. Biochem J. 2006 Aug
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Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN,
Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron
B, Isakoff SJ, Brugge JS, LaBaer J. Functional proteomics
approach to investigate the biological activities of cDNAs
implicated in breast cancer. J Proteome Res. 2006
Mar;5(3):599-610
Fukushima N, Shano S, Moriyama R, Chun J.
Lysophosphatidic acid stimulates neuronal differentiation of
cortical neuroblasts through the LPA1-G(i/o) pathway.
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Murph MM, Hurst-Kennedy J, Newton V, Brindley DN,
Radhakrishna H. Lysophosphatidic acid decreases the nuclear
localization and cellular abundance of the p53 tumor
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Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P,
Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra
JP. LPA1 receptor activation promotes renal interstitial fibrosis.
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Pradère JP, Gonzalez J, Klein J, Valet P, Grès S, Salant D,
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Lysophosphatidic acid and renal fibrosis. Biochim Biophys
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Estivill-Torrús G, Llebrez-Zayas P, Matas-Rico E, Santín L,
Pedraza C, De Diego I, Del Arco I, Fernández-Llebrez P, Chun
J, De Fonseca FR. Absence of LPA1 signaling results in
defective cortical development. Cereb Cortex. 2008
Apr;18(4):938-50
Urs NM, Kowalczyk AP, Radhakrishna H. Different
mechanisms regulate lysophosphatidic acid (LPA)-dependent
versus phorbol ester-dependent internalization of the LPA1
receptor. J Biol Chem. 2008 Feb 29;283(9):5249-57
Yu S, Murph MM, Lu Y, Liu S, Hall HS, Liu J, Stephens C,
Fang X, Mills GB. Lysophosphatidic acid receptors determine
tumorigenicity and aggressiveness of ovarian cancer cells. J
Natl Cancer Inst. 2008 Nov 19;100(22):1630-42
Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A,
Windle JJ, Chen CK, Fang X. Role of LPA4/p2y9/GPR23 in
negative regulation of cell motility. Mol Biol Cell. 2008
Dec;19(12):5435-45
Obo Y, Yamada T, Furukawa M, Hotta M, Honoki K,
Fukushima N, Tsujiuchi T. Frequent mutations of
lysophosphatidic acid receptor-1 gene in rat liver tumors. Mutat
Res. 2009 Jan 15;660(1-2):47-50
Mototani H, Iida A, Nakajima M, Furuichi T, Miyamoto Y,
Tsunoda T, Sudo A, Kotani A, Uchida A, Ozaki K, Tanaka Y,
Nakamura Y, Tanaka T, Notoya K, Ikegawa S. A functional
SNP in EDG2 increases susceptibility to knee osteoarthritis in
Japanese. Hum Mol Genet. 2008 Jun 15;17(12):1790-7
Yamada T, Obo Y, Furukawa M, Hotta M, Yamasaki A, Honoki
K, Fukushima N, Tsujiuchi T. Mutations of lysophosphatidic
acid receptor-1 gene during progression of lung tumors in rats.
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Murph MM, Nguyen GH, Radhakrishna H, Mills GB.
Sharpening the edges of understanding the structure/function
of the LPA1 receptor: expression in cancer and mechanisms of
regulation. Biochim Biophys Acta. 2008 Sep;1781(9):547-57
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Murph MM, Radhakrishna H. LPAR1 (lysophosphatidic acid
receptor 1). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):289-292.
292
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PIK3CA (phosphoinositide-3-kinase, catalytic,
alpha polypeptide)
Montserrat Sanchez-Cespedes
Programa d'Epigenetica i Biologia del Cancer-PEBC, Institut d'Investigacions Biomediques Bellvitge
(IDIBELL), Hospital Durant i Reynals, Avinguda Gran Via de l'Hospitalet, 199-203 08907-L'Hospitalet de
Llobregat-Barcelona, Spain (MSC)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/PIK3CAID415ch3q26.html
DOI: 10.4267/2042/44713
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(gi 5931525), the later one in the Cat Eye Syndrome
region. These regions are highly homolog to the
sequences of exons 9 and 11-13 of the PIK3CA gene.
Identity
Other names: EC 2.7.1.153; MGC142161;
MGC14216
PI3K; p110-alpha
HGNC (Hugo): PIK3CA
Location: 3q26.32
Local
order:
centromere-KCNMB2-ZMAT3BC032034-PIK3CA-KCNMB3-ZNF639-MFN1GNB4- telomere
Transcription
The human PIK3CA transcript has an open reading
frame of 3,207-bp, predicting a protein of 1,068 amino
acid residues.
Protein
Description
DNA/RNA
The PIK3CA gene encodes the p110alpha protein
which is a catalytic subunit of the class I PI 3-kinases
(PI3K). Class I PI3K are heterodimeric molecules
composed of a catalytic subunit, a p110, and a
regulatory subunit. There are three possible calatytic
subunits p110alpha, beta or delta.
Relative size of the 21 exons of PIK3CA. The entire exon 1 is
UTR (untranslated region). Exon numeration corresponds to the
prevalent transcript (NM-006218).
Description
Expression
The PIK3CA gene spans a total genomic size of 86,190
bases and is composed of 21 exons, 20 of them coding
exons of varying lengths. Putative pseudogenes of
PIK3CA have been described on chromosomes 16 (gi
28913054) and 22q11.2
Widely expressed.
Localisation
The p110alpha localizes in the cytoplasm.
p110alpha conserved domains. Through its adaptor binding domain p110alpha interacts with the regulatory subunit. C2 domain, proteinkinase-C-homology-2 domain.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
293
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide)
Sanchez-Cespedes M
tion has also been proposed as a mechanism for
oncogene activation in some tumors (Angulo et al.,
2008). Because PIK3CA is now considered an
important oncogene implicated in the development of a
wide variety of human cancers, efforts are now being
directed towards the development of mole-cules that
inhibit the activity of PI3K (Garcia-Echeverria et al.,
2008). These could be efficient in the treatment of
those tumors carrying constitutive activation of PI3K
pathway. PTEN is a well known tumor suppressor that
counteracts the action of PI3K by dephosphorylating
the phosphoinositide-3,4,5-trisphosphate (PIP3). Thus,
the treatment with drugs that inhibit p110alpha activity
would be also potentially efficient in patients whose
tumors carry genetic alterations at PTEN.
It has recently been reported that activation of the PI3K
pathway in breast tumors with concomitant ERBB2
gene amplification, either through PIK3CA mutations
or PTEN inactivation, underlies trastuzumab resistance.
These findings may provide a biomarker to identify
patients unlikely to respond to trastuzumab-based
therapy (Berns et al., 2007).
Function
Class I PI 3-kinases (PI3K) are linked to many cellular
functions, including cell growth, prolifera-tion,
differentiation, motility, survival and intra-cellular
trafficking. PI3K convert PI(4,5)P2 to PI(3,4,5)P3 on
the inner leaflet of the plasma membrane. The
PI(3,4,)P3 provokes the recruitment to cellular
membranes of a variety of signalling proteins,
containing PX domain, pleckstrin homo-logy domains
(PH domains), FYVE domains and other
phosphoinositide-binding domains. One of these is the
protein kinase B (PKB/AKT) a very well known
protein that is activated as a result of its translocation to
the cell membrane where it is then phosphorylated and
activated by another kinase, called phosphoinositide
dependent kinase 1 (PDK1). The phosphorylation of
AKT leads to the activation of the TSC/mTOR
pathway. PTEN, a tumor suppressor inactivated in
many cancers counteracts the action of PI3K by
dephosphoryla-ting
the
phosphoinositide-3,4,5trisphosphate (PIP3) (Lee et al., 2007).The PI3K are
inhibited by the drugs wortmannin and LY294002
although to various degree of sensitivity among the
different classes.
To be noted
Note
Recent evidence has shown that the PIK3CA gene is
mutated and amplified in a range of human cancers.
Due to that p110alpha is believed to be a promising
drug target. A number of pharmaceutical companies are
currently designing and charactering potential
p110alpha isoform specific inhibitors.
Mutations
Somatic
Somatic mutations at the PIK3CA gene have been
found in tumors and thus, it can be considered a bona
fide oncogene (Samuels et al., 2004). Most of the
mutations cluster in hotspots within the helical or the
catalytic domains.
References
Implicated in
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S,
Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK,
Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High
frequency of mutations of the PIK3CA gene in human cancers.
Science. 2004 Apr 23;304(5670):554
A wide variety of human cancers
Note
(For example, colon, breast, endometrial, ovarian,
brain, lung, thyroid, head and neck and stomach).
PIK3CA mutations lead to constitutive activation of
p110alpha enzymatic activity, stimulate AKT
signaling, and allow growth factor-independent growth
(Bader et al., 2005). In addition, when expressed in
normal cells, these mutations allow anchorageindependent growth, further attesting to their important
role in cancer development (Kang et al., 2005).
PIK3CA somatic mutations are frequent in a variety of
human primary tumors and cancer cell lines such as,
among others, those of the colon, breast, and stomach
(Samuels et al., 2004). However, in other tumors, i.e.
those of the lung, head and neck, brain, endometrium,
ovary, prostate, osteosarcoma and pancreas,
hematopoietic malignancies, PIK3CA mutations are not
as common (Angulo et al., 2008; Qiu et al., 2006;
Muller et al., 2007; Samuels et al., 2004; Schonleben et
al., 2006). PIK3CA gene amplifica-
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K
deregulates transcription and translation. Nat Rev Cancer.
2005 Dec;5(12):921-9
Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase
mutations identified in human cancer are oncogenic. Proc Natl
Acad Sci U S A. 2005 Jan 18;102(3):802-7
Qiu W, Schönleben F, Li X, Ho DJ, Close LG, Manolidis S,
Bennett BP, Su GH. PIK3CA mutations in head and neck
squamous cell carcinoma. Clin Cancer Res. 2006 Mar
1;12(5):1441-6
Schönleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD,
Remotti HE, Su GH. PIK3CA mutations in intraductal papillary
mucinous neoplasm/carcinoma of the pancreas. Clin Cancer
Res. 2006 Jun 15;12(12):3851-5
Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans
EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K,
Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ,
Bernards R. A functional genetic approach identifies the PI3K
pathway as a major determinant of trastuzumab resistance in
breast cancer. Cancer Cell. 2007 Oct;12(4):395-402
294
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide)
Sanchez-Cespedes M
Lee JY, Engelman JA, Cantley LC. Biochemistry. PI3K charges
ahead. Science. 2007 Jul 13;317(5835):206-7
PIK3CA overexpression by gene amplification. J Pathol. 2008
Feb;214(3):347-56
Müller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS,
Kawamata N, Luong QT, Koeffler HP. Rare mutations of the
PIK3CA gene in malignancies of the hematopoietic system as
well as endometrium, ovary, prostate and osteosarcomas, and
discovery of a PIK3CA pseudogene. Leuk Res. 2007
Jan;31(1):27-32
Garcia-Echeverria C, Sellers WR. Drug discovery approaches
targeting the PI3K/Akt pathway in cancer. Oncogene. 2008
Sep 18;27(41):5511-26
This article should be referenced as such:
Sanchez-Cespedes M. PIK3CA (phosphoinositide-3-kinase,
catalytic, alpha polypeptide). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(3):293-295.
Angulo B, Suarez-Gauthier A, Lopez-Rios F, Medina PP,
Conde E, Tang M, Soler G, Lopez-Encuentra A, Cigudosa JC,
Sanchez-Cespedes M. Expression signatures in lung cancer
reveal a profile for EGFR-mutant tumours and identify selective
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
295
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
SFRP4 (Secreted Frizzled-Related Protein 4)
Kendra S Carmon, David S Loose
University of Texas Health Science Center Houston, Houston, TX 77030, USA (KSC, DSL)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/SFRP4ID42277ch7p14.html
DOI: 10.4267/2042/44714
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
The SFRP4 mRNA transcript is 2974 bp, 1041 bp are
coding sequence. Ensembl data predicts a second
transcript from the SFRP4 gene, lacking the 81 bp exon
2, although this has not been demons-trated.
Other names: FRP-4; sFRP-4; FRPHE; MGC26498;
LOC6424
HGNC (Hugo): SFRP4
Location: 7p14.1
Local order: According to NCBI, SFRP4 is telomeric
to EPDR1 (7p14.1) ependymin related protein 1
(zebrafish) and STARD3NL (7p14-p13) StAR-related
lipid transfer domain containing 3 N-terminal like and
centromeric to TXNDC3 (7p14.1) thioredoxin domain
containing 3 (spermatozoa) and GPR141 (7p14.1) G
protein-coupled receptor 141.
Protein
Description
SFRP4 protein is comprised of 346 amino acids with a
predicted molecular weight of 39.9 kDa and an actual
molecular weight of approximately 50-55 kDa.
SFRP4 belongs to a family of five SFRPs; these
proteins fold into two independent domains. The Nterminus contains a secretion signal peptide followed
by a ~120 amino acid cysteine-rich domain (CRD). The
CRD is 30-50% identical to the extracellular putative
Wnt-binding domain of frizzled (Fzd) receptors and is
characterized by the presence of ten cysteine residues at
conserved positions.
DNA/RNA
Description
The SFRP4 gene spans 10.99 kb on the short arm of
chromosome 7 and is transcribed from the minus strand
in the centromere-to-telomere orientation. The gene is
encoded by six exons with the trans-lation initiation
codon in the first exon.
Diagram illustrates SFRP4 gene that contains a total of six exons.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
296
SFRP4 (Secreted Frizzled-Related Protein 4)
Carmon KS, Loose DS
Diagram illustrates the full length SFRP4 protein which contains a signal peptide sequence of 20-30 amino acids, a cysteine-rich domain
(CRD) of approximately 120 amino acids, and a netrin-related motif (NTR) domain. Conserved cysteines of the CRD are indicated by *.
These cysteines form a pattern of disulfide bridges. The
C-terminal portion of the SFRP protein is characterized
by segments of positively charged residues that appear
to confer heparin-binding properties in at least two
SFRPs (SFRP1 and SFRP3) and contains a netrinrelated motif (NTR) with six cysteine residues that
most likely form three disulfide bridges. NTR domains
with similar features are found in a wide range of
unrelated proteins, including Netrin-1, tissue inhibitors
of metallo-proteinases (TIMPs), complement proteins
and type I procollagen C-proteinase enhancer proteins
(PCOLCEs). The six conserved cysteines in the NTR
of SFRP4 share a similar spacing to SFRP3, whereas
those of the SFRP1/SFRP2/SFRP5 subgroup are
distinctively different, indicating a disparity in disulfide
bond formation. Uniquely, SFRP4 contains two
additional cysteine residues. The overall function of the
NTR is unknown, yet there is some evidence that the
NTR may also play a role in Wnt binding. This implies
that multiple Wnt binding sites may exist on SFRP
molecules and/or that SFRPs exhibit differential
affinities for Wnt ligands according to the different
SFRP
conformational
and
post-translational
modifications.
adult uterine morphology and function. SFRP4 has
been shown to increase apoptosis during ovulation.
Transgenic studies have found that SFRP4 decreases
bone formation and inhibits osteoblast proliferation by
attenuating canonical/beta-catenin-Wnt
signaling.
SFRP4 reportedly exhibits phospha-turic effects by
specifically inhibiting sodium-dependent phosphate
uptake.
Expression
SFRP4 is expressed in various normal tissues including
endometrium (specifically stromal cells with higher
expression during proliferative phase of menstrual
cycle), ovary, kidney, heart, brain, mammary gland,
cervix, pancreas, stomach, colon, lung, skeletal muscle,
testis, eye, bone, prostate, and liver.
Note
SFRP4 was more frequently down-regulated in
(microsatellite instability). MSI cancers as compared
with (microsatellite stable) MSS endo-metrioid
endometrial cancers. Expression of SFRP4 is decreased
in both low-grade endometrial stromal sarcoma and
undifferentiated endometrial sarcoma.
Localisation
Malignant Pleural Mesothelioma
Secreted from cell; extracellular matrix; bound to
plasma membrane.
Note
SFRP4 promoter is frequently methylated in this cancer
leading to inhibition of expression and is associated
with abnormal growth; restoration of SFRP4 results in
growth suppression and apoptosis in mesothelioma cell
lines.
Homology
Of the five human SFRPs (SFRP1, SFRP2, SFRP3,
SFRP4, SFRP5), SFRP4 shares most significant
homology with SFRP3.
Mutations
Note
It was reported that the T allele of the SFRP4 gene
polymorphism ARG262 (CGC to CGT) of exon4 is
associated with decreased bone mineral density in postmenopausal Japanese women.
Implicated in
Endometrial Carcinoma
Function
Since SFRPs share a similar CRD with the Fzd family
of receptors; it is believed that SFRPs may act as
soluble modulators that compete with Fzd to bind the
Wnt ligands, thereby altering the Wnt signal. Individual
SFRPs also have distinct binding specificity for distinct
Wnt ligands. Reports have demonstrated that SFRP4
binds Wnt7a and there is conflicting data for SFRP4
binding to Wnt3a. SFRP4 expression is regulated by
estrogen and progesterone and may act as a regulator of
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Tumor-induced osteomalacia
Note
Tumor-induced osteomalacia is a disorder in which
there is an increase in renal phosphate excretion and a
reduction in serum phosphate levels leading to
hyperphosphaturia, hypophosphatemia and rickets.
297
SFRP4 (Secreted Frizzled-Related Protein 4)
Carmon KS, Loose DS
CLUSTAL alignment of the 5 human SFRPs.
SFRP4 is highly expressed in such tumors and
functions as a circulating phosphaturic factor that
antagonizes renal Wnt-signaling.
tumors of cancer patients versus matched adjacent
tissue controls.
Breast Cancer
Note
Studies have found evidence for SFRP4 overexpression
in breast cancer.
Note
The SFRP4 was highly methylated in gastric carcinoma
samples with greater instance in H. pylori positive
patients.
Pancreatic Cancer
Prostate Cancer
Note
SFRP4 found to be significantly hypermethylated in the
Note
SFRP4 is overexpressed in prostate cancers and
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Gastric Carcinoma
298
SFRP4 (Secreted Frizzled-Related Protein 4)
Carmon KS, Loose DS
Yamaguchi TP. Heads or tails: Wnts and anterior-posterior
patterning. Curr Biol. 2001 Sep 4;11(17):R713-24
functions to inhibit cell proliferation and metastatic
potential.
Prognosis
Increased expression of membranous SFRP4 is
associated with a good prognosis in human localized
androgen-dependent prostate cancer, suggesting a role
for sFRP4 in early stage disease.
Chong JM, Uren A, Rubin JS, Speicher DW. Disulfide bond
assignments of secreted Frizzled-related protein-1 provide
insights about Frizzled homology and netrin modules. J Biol
Chem. 2002 Feb 15;277(7):5134-44
Fujita M, Ogawa S, Fukuoka H, Tsukui T, Nemoto N, Tsutsumi
O, Ouchi Y, Inoue S. Differential expression of secreted
frizzled-related protein 4 in decidual cells during pregnancy. J
Mol Endocrinol. 2002 Jun;28(3):213-23
B-cell chronic lymphocytic leukemia
Note
SFRP4 was found to be frequently methylated and
downregulated in CLL samples.
Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D,
Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R. Secreted
frizzled-related protein 4 is a potent tumor-derived
phosphaturic agent. J Clin Invest. 2003 Sep;112(5):785-94
Colorectal Carcinoma
Drake JM, Friis RR, Dharmarajan AM. The role of sFRP4, a
secreted frizzled-related protein, in ovulation. Apoptosis. 2003
Aug;8(4):389-97
Note
SFRP4 expression was shown to be up-regulated in
colorectal cancer.
Ace CI, Okulicz WC. Microarray profiling of progesteroneregulated endometrial genes during the rhesus monkey
secretory phase. Reprod Biol Endocrinol. 2004 Jul 7;2:54
Esophageal Adenocarcinoma
Note
SFRP4 mRNA and protein expression were
significantly decreased due to hypermethylation in
esophageal adenocarcinoma and Barrett's esophagus
patients.
Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi
T, Orimo H, Ouchi Y, Inoue S.. Association of a single
nucleotide polymorphism in the secreted frizzled-related
protein 4 (sFRP4) gene with bone mineral density. Ger.
Geront. Int. 2004; 4 (3): 175-180.
Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS,
Golovsky D, Brenner PC, O'Neill GF, Kooner R, Stricker PD,
Grygiel JJ, Sutherland RL. Membranous expression of
secreted frizzled-related protein 4 predicts for good prognosis
in localized prostate cancer and inhibits PC3 cellular
proliferation in vitro. Clin Cancer Res. 2004 Jan 15;10(2):61525
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Mazieres J, Mikami I, McCormick F, Jablons DM. Secreted
frizzled-related protein 4 is silenced by hypermethylation and
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Bányai L, Patthy L. The NTR module: domains of netrins,
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Zou H, Molina JR, Harrington JJ, Osborn NK, Klatt KK,
Romero Y, Burgart LJ, Ahlquist DA. Aberrant methylation of
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adenocarcinoma and Barrett's esophagus. Int J Cancer. 2005
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Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro
DP, Cumberledge S, Rubin JS. Secreted frizzled-related
protein-1 binds directly to Wingless and is a biphasic modulator
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This article should be referenced as such:
Bu XM, Zhao CH, Zhang N, Gao F, Lin S, Dai XW.
Hypermethylation and aberrant expression of secreted frizzledrelated protein genes in pancreatic cancer. World J
Gastroenterol. 2008 Jun 7;14(21):3421-4
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Carmon KS, Loose DS. SFRP4 (Secreted Frizzled-Related
Protein 4). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):296-300.
300
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral
oncogene homolog (avian))
Stephen Hiscox
Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff, UK (SH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/SRCID448ch20q11.html
DOI: 10.4267/2042/44715
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: ASV (Avian Sarcoma Virus); SRC1; cSRC; p60-Src; pp60c-Src
HGNC (Hugo): SRC
Location: 20q11.23
Note
The Src kinase proto-oncogene has a high degree of
similarity to the v-src gene of Rous sarcoma virus,
although the C-terminal domain of v-Src is trunca-ted
and lacks the regulatory Tyr527 and therefore is not
subjected to downregulation by Csk. Src kinase is
implicated in the regulation of embryonic development,
cell differentiation and proliferation. Src has been
suggested to play a key role in cancer, where it may
facilitate tumour spread through promotion of tumour
cell invasion.
Note
Src can be phosphorylated on Tyr-530 by CSK (c-Src
kinase). The phosphorylated form is termed pp60c-src.
Phosphorylation of this tyrosine allows facilitates
interaction between the C-terminal tail and the SH2
domain, maintaining Src in an inactive formation.
Protein Translation:
MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFP
ASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGF
NSSDTVTSPQRAGPLAGGVTTFVALYDYESRTET
DLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGY
IPSNYVAPSDSIQAEEWYFGKITRREGQGCFGEV
WMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQV
MKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLL
DFLKGETGKYLRLPQLVDMAAQIASGMAYVER
MNYVHRDLRAANILVGENLVCKVADFGLARLIE
DNEYTARQGAKFPIKWTAPEAALYGRFTIKSDV
WSFGILLTELTTKGRVPYPGMVNREVLDQVERG
YRMPCPPECPESLHDLMCQCWRKEPEERPTFEYL
QAFLEDYFTSTEPQYQPGENL
Note: This variant (isoform 1) represents the longer Src
transcript although both isoforms 1 and 2 encode the
same protein as the difference is in the 5' UTR.
DNA/RNA
Note
The gene consists of 14 exons. Two isoforms have been
described differing in their 5' UTRs. Variant 1
represents the longer transcript although both isoforms
1 and 2 encode the same protein.
Description
Size: 61.33 Kb, 14 exons. mRNA: 4145 bases.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
301
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian))
Hiscox S
Linear representation of the protein structure of human Src family members, showing the six distinct domains. N and C denote N- and Ctermini respectively. Location of major regulatory phosphorylation sites and the myristolation signal sequence are shown.
transcription events. The ability of Src to function as
both an effector and regulator of receptor-induced
signalling allows it to mediate cross-talk between
normally distinct signalling pathways and thus regulate
a wide variety of both normal and oncogenic processes,
including proliferation, differentiation, survival,
adhesion, motility, invasion and angiogenesis.
Description
Size: 536 amino acids; 59.835 KDa.
Src is 59.6 KDa in size and has a domain structure
comprised of six distinct functional regions (see figure
above). These include an N-terminal SH4 domain that
contains a lipid-modification sequence allowing
targeting of Src to cellular membranes, and an adjacent,
poorly-conserved region thus being unique to each Src
family member. SH3 and SH2 domains adjacent to the
N-terminus facilitate protein-protein interactions
between Src and its interacting proteins whilst the SH1
domain allows ATP and substrate binding and has
tyrosine kinase activity; autophosphorylation of Y419
within this domain is required for the maximum kinase
activity of Src. The negative regulatory tail of Src
contains a tyrosine at 530, the phosphorylation of
which promotes a conformational change to produce an
inactive Src molecule. Sequences within the Cterminus of Src have been recently identified to
facilitate protein-protein interactions have been shown
to regulate Src function in addition to its kinase
activity.
Homology
c-Src is the prototypic member of a family of nine nonreceptor tyrosine kinases which share the same domain
structure (Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr and
Frk) (Erpel and Courtneidge, 1995) and are expressed
in vertebrates. All Src family members have the same
basic structure of an N-terminal, unique domain
containing a myristylation site and frequently a
palmitoylation site; regulatory SH3 and SH2 domains;
a catalytic domain that has its active site wedged
between the two lobes of the molecule, and a Cterminal regulatory tail that contains the hallmark
regulatory tyrosine residue (Tyr527 in Src). The
activity of Src family kinases is suppressed upon
phosphorylation of Tyr527, allowing binding of the Cterminal domain to the SH2 domain. The SH2 and SH3
domains bind phosphotyrosine and proline-rich
peptides, respectively; through these interactions, they
participate in intra- and intermolecular regulation of
kinase activity, as well as localization and substrate
recognition. Differences in the SH2 linker sequences
within Src family kinases correlate with the division of
the Src kinase family into two separate subfamilies:
Group A: Src, Fyn, Yes, Fgr and Group B: Lyn, Hck,
Lck and Blk. Frk forms a separate but linked subfamily
but with homologues also found in invertebrates. Src
family members, with the exception of Src, Fyn and
Yes, exhibit tissue-restricted distribution, being found
primarily in cells of a haematopoietic nature. Below is
a table constructed from Src homology analysis
performed by CluSTr:
Expression
Ubiquitously expressed but with particularly high
levels in brain tissue, osteoclasts and platelets.
Localisation
Predominantly cytoplasmic and/or plasma mem-brane,
the latter due to myristolation of the N-terminus.
Activated Src has also been reported in the cell nucleus
in some tumour tissues.
Function
Src can interact with a diverse array of cellular factors
allowing it to regulate a variety of normal and
oncogenic processes that ultimately result in cell
proliferation, differentiation, survival, adhe-sion,
motility, invasion and angiogenesis (Thomas and
Brugge, 1997; Summy and Gallick, 2003). Such
interacting partners include receptor tyrosine kinases
(e.g. the EGF receptor family (Biscardi et al., 1998)),
integrins (Galliher and Schiemann, 2006; Huveneers et
al., 2007), cell-cell adhesion molecules (Giehl and
Menke, 2008), in addition to STATs (Silva, 2004),
FAK (Brunton and Frame, 2008), the adaptor protein
p130Cas (Chang et al., 2008) and GPCRs (McGarrigle
and Huang, 2007). Importantly, Src can also interact
with the oestrogen receptor (Weatherman, 2008), where
it has been shown to be pivotal in both non-genomic
ER activation of signalling pathways and gene
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
302
Src family
member
% identity*
% similarity**
Fyn
75
10
Yes
73
9
Fgr
66
11
Lck
60
17
Lyn
60
17
Hck
57
17
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian))
Blk
62
family allowing Src to regulate signal-ling pathways
that may contribute to aggressive breast cancer cell
behaviour. Src is also intimately involved with Her2
pathway signalling in breast cancer, the result of which
is the promotion of an invasive phenotype (Vadlamudi
et al., 2003; Tan et al., 2005).
Oestrogenic signalling plays a critical role in promoting
breast cancer cell growth where ligand-induced
activation of oestrogen receptors (ERs) results in gene
transcription mediated by the ER, in complex with
various co-activators/co-repressor molecules. In such
cases, Src is able to potentiate ER-mediated, AF-1
dependent gene transcription through indirect
phosphorylation of nuclear ER via ERK1/ERK2 (Feng
et al., 2001) and Akt (Campbell et al., 2001; Shah et al.,
2005) and through regulation of FAK-p130CAS-JNK
signalling pathway activity and the subsequent
activation of co-activator molecules including CBP
(PAG1) and GRIP1 (NCOA2). Furthermore, Src
appears to mediate non-genomic ER signalling through
ERK and Akt pathways (Castoria et al., 2001; Wessler
et al., 2006) to regulate cellular proliferation and
survival (Castoria et al., 1999; Migliaccio et al., 2000).
That Src is involved in both EGFR/Her2 and ER
signalling has led to Src being implicated in growth
factor-ER cross talk mechanisms in breast cancer and
the development of endocrine resistance (Arpino et al.,
2008; Massarweh and Schiff, 2006; Hiscox et al., 2006;
Hiscox et al., 2009).
13
*Percent identity between Src and protein; defined as: (Same
AAs/Length of Protein 1) X100%
**Percent similarity between Src and protein; defined as: (Sim.
AAs/Length of Protein 1) X100%
Mutations
Somatic
The SRC family of kinases is rarely mutated in primary
human tumours, although apparently scarce, a
truncating and activating mutation in Src (at aa 531)
has been described for a small subset of advanced-stage
colorectal cancers (Irby et al., 1999).
Implicated in
Cancer
Note
Elevated Src expression and/or activity has been
reported in many different cancer types, where it may
associate with poor clinical prognosis (Irby and
Yeatman, 2000). Increased Src kinase activity in cancer
is likely to arise from the deregulation of Src
expression and/or activation mechanisms rather than
the presence of activating mutations, since genetic
mutations of this kind are rarely reported for Src (see
above). Whereas constitutively activated forms of Src
are transforming, wild-type Src has a relatively low
transformation potential suggesting that Src may act to
facilitate intracellular signalling through regulation,
either directly or indirectly, of other signalling proteins.
Hematopoietic cancers
Disease
The majority of Src family kinases are highly expressed
in cells of a hematopoietic origin where they are
suggested to regulate growth and prolifera-tion. Src
itself is, along with related family kinase members, are
implicated in imatinib-resistant, BCR-ABL-expressing
CML (Li, 2008).
Colorectal cancer
Disease
Increased Src activity has been widely described in
colorectal tumour tissue compared with normal
epithelia and within colon polyps, particularly those
displaying a malignant phenotype (DeSeau et al., 1987;
Cartwright et al., 1994). In colorectal cancer tissue
studies, elevated Src kinase activity is associated with a
poor clinical outcome (Aligayer et al., 2002). In vitro
studies suggest that in colon cancer, Src may contribute
more to disease spread than to increased proliferation
(Jones et al., 2002).
Other tumour types
Disease
Src protein and activity have been identified as being
increased in a number of other tumour types including
gastric, pancreatic, lung and ovarian tumours compared
to normal tissue suggesting a possible role for Src in
these tumours.
References
Breast cancer
Disease
Src kinase activity is increased in breast cancer tissue
compared to normal tissues (Verbeek et al., 1996). In
vivo animal models suggest that Src activity is elevated
in breast tumours over-expressing HER2 and
interaction between Src and erbB family members may
promote the develop-ment of a more aggressive disease
clinically (Biscardi et al., 2000; Tan et al., 2005).
Physical interactions between Src and growth factor
receptors are reported in breast cancer tissues and cells,
particularly with receptor tyrosine kinases of the EGFR
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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1995 Apr;7(2):176-82
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Thomas SM, Brugge JS. Cellular functions regulated by Src
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Galliher AJ, Schiemann WP. Beta3 integrin and Src facilitate
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Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano
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Irby RB, Yeatman TJ. Role of Src expression and activation in
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Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio
A, Lombardi M, Barone MV, Ametrano D, Zannini MS,
Abbondanza C, Auricchio F. Steroid-induced androgen
receptor-oestradiol receptor beta-Src complex triggers prostate
cancer cell proliferation. EMBO J. 2000 Oct 16;19(20):5406-17
Huveneers S, van den Bout I, Sonneveld P, Sancho A,
Sonnenberg A, Danen EH. Integrin alpha v beta 3 controls
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McGarrigle D, Huang XY. GPCRs signaling directly through
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Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk
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304
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
TACC3 (transforming, acidic coiled-coil containing
protein 3)
Melissa R Eslinger, Brenda Lauffart, Ivan H Still
Department of Chemistry and Life Science Bartlett Hall, United States Military Academy, West Point, New
York 10996, USA (MRE), Department of Physical Sciences, Arkansas Tech University, 1701 N Boulder
Ave, Russellville, AR 72801, USA (BL), Department of Biological Sciences, Arkansas Tech University,
1701 N Boulder Ave, Russellville, AR 72801, USA (IHS)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TACC3ID42458ch4p16.html
DOI: 10.4267/2042/44716
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: ERIC1; MGC117382; MGC133242
HGNC (Hugo): TACC3
Location: 4p16.3
exons between exon 1 and the first coding exon (exon
2), based on NM_006342, is indicated based on several
cDNAs that may however be from suspect cDNA
libraries (see UCSC Genome Bioinformatics Site
(http://genome.ucsc.edu)). Four additional transcripts
variants are suggested based on singleton Expressed
sequence tags in tumor cell lines (AW516785,
BE552327, BX331864) and/or stem cell progenitors
(AV761182, CX872433).
DNA/RNA
Description
The gene is composed of 16 verified exons spanning
23.6 kb.
Transcription
Encodes a single confirmed 2788 nt transcript
(NM_006342) (Still et al., 1999), although one
additional transcript with two additional small 5' coding
Pseudogene
None.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
305
TACC3 (transforming, acidic coiled-coil containing protein 3)
Eslinger MR, et al.
SDS-PAGE. Additional variants are suggested based
on singleton cDNAs (see above) but their predicted
protein isoforms have not been confirmed.
Protein
Description
Expression
TACC3 encodes a single protein of 838 amino acids
with a molecular mass of 90 kDa (Still et al., 1999).
The protein is heavily phosphorylated based on direct
evidence and based on predictions from the Xenopus
and mouse orthologs (Beausoleil et al., 2004;
Beausoleil et al., 2008; Kinoshita et al., 2005; Yu et al.,
2007; Cantin et al., 2008; Dephoure et al., 2008). Thus,
human TACC3 migrates at approxi-mately 150 kDa in
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
High levels during early (mouse) embryogenesis, in
particular during early differentiation of specific tissues
(Sadek et al., 2003). In adult tissues, expression is
relatively limited, with high levels noted in
hematological tissues such as the thymus, spleen and
leukocytes, and reproductive tissues, especially meiotic
cells of the testes and ovary (Still et al., 1999; Sadek et
al., 2003).
306
TACC3 (transforming, acidic coiled-coil containing protein 3)
Eslinger MR, et al.
Epithelial layers of the lung, mammary gland and ovary
express TACC3 and alterations in expression are noted
during tumorigenesis (see below). Expression in human
adult tissues is summarized in Lauffart et al. 2006.
targets for cyclin dependent kinases in mitotic HeLa
cells (Yu et al., 2007; Cantin et al., 2008; Dephoure et
al., 2008). By homology, Ser558 phosphorylation by
TPX2 is required for nucleation of microtubules in
meiotic oocytes (Brunet et al., 2008).
TACC3 also has a defined role in interphase cells as a
transcriptional cofactor for the aryl-nuclear translocator
protein (Sadek, 2000), FOG1 (Garriga-Canut and
Orkin, 2004; Simpson et al., 2004) and is a possible
indirect activator of CREB via FHL family of
coactivator/corepressor proteins (Lauffart et al.,
2007b). Roles in transcriptional regulation
Localisation
Human (and mouse) TACC3 is located in the
interphase nucleus and/or cytosol, depending on cell
type and cancer type (Gergely et al., 2000; Aitola et al.,
2003; Lauffart et al., 2005; Jung et al., 2006;
Vettaikkorumakankauv et al., 2008). TACC3 does not
however contain a classical nuclear localisation signal
(Still et al., 1999). TACC3 associates with the
centrosome in a cell cycle dependent manner (Gergely
et al., 2000). Phosphorylation of TACC3 by Aurora A
on key serine residues is required for this interaction
(Kinoshita et al., 2005; LeRoy et al., 2007).
Overexpression of TACC3 from artificial constructs
can result in accumulation in the cytosol of some cells
resulting in oligmerisation in punctate structures
(Gergely et al., 2000).
have also been proposed based on TACC3 binding to
GAS41 (YEATS4) via the SDP repeat, histone acetyl
transferases hGCN5L2 (KAT2A), pCAF (KAT2B),
and retinoid X-receptor beta via the TACC domain
(Gangisetty,
2004;
Lauffart
et
al.,
2002;
Vettaikkorumakankauv et al., 2008). TACC3
functionally interacts with MBD2 bound to methylated
promoters, promoting transcription by displacement of
HDAC2 and recruitment of KAT2B (Angrisano et al.,
2006). Human TACC3 may be involved in
transcriptional termination and/or pre-mRNA splicing
through TTF2 (Leonard et al., 2003). TACC3 can
interact with BARD1, BRCA1 and p53 and has been
shown to have some protective affects against
adriamycin-mediated DNA damage in ovarian cancer
cells (Lauffart et al., 2007a). Phosphorylation of the
last amino acid of the SDP repeat, Ser434, is noted in
nuclear extracts of HeLa (Beausoleil, 2004; Beausoleil,
2006), although its functional significance is unknown.
Function
Gene knockout and knockdown studies in mouse have
indicated that TACC3 is vital for embryonic
development. A functionally null TACC3 mutant dies
during mid to late gestation due to excessive apoptosis
affecting hematopoietic and other organ systems
(Piekorz et al., 2002). Hypomorphic alleles result in
defects in mitosis affecting mesenchymal sclerotome
and therefore the axial skeleton (Yao et al., 2007).
These mutational mouse models indicate that TACC3
has a role in chromosomal alignment, separation and
cytokinesis and that TACC3 can be associated with
p53-mediated apoptosis.
TACC3 has a well characterized function in
microtubule dynamics, particularly during mitosis,
based on mutational analysis (see above) and physical
interactions with Aurora A and Aurora B kinases,
CKAP5 (ch-TOG/XMAP215) and AKAP9 via the
TACC domain (see Peset and Vernos, 2008 for
review). Interaction with CEP120 is important in
interkinetic nuclear migration and maintenance of
neural progenitor self-renewal during the development
of the neocortex (Xie et al., 2007). Phosphorylation of
Ser34, Ser552 and Ser558 by Aurora A are required for
localization to centro-somes and is necessary for
recruitment of CKAP5 and nucleation of microtubules
(Kinoshita et al., 2005; LeRoy et al., 2007). Ser25,
Thr59, Ser71, Ser317, and Ser 434 are presumed
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Homology
Member of the TACC family, based on the presence of
the evolutionarily conserved approximately 200 amino acid carboxy terminal coiled coil
domain (TACC domain) (Still et al., 1999; Still et al.,
2004). TACC3 orthologues are noted in all vertebrates
sequenced to date (Still et al., 2004 and Still
unpublished). However, the central region between the
conserved N-terminal region and the TACC domain is
highly variable in size and sequence. The SDP repeats
are noted within the central region in most vertebrates
except mouse and rat (Still et al., 2004).
Mutations
Note
Somatic mutations noted in ovarian cancer samples
(Lauffart et al., 2005; Eslinger, 2006).
307
TACC3 (transforming, acidic coiled-coil containing protein 3)
Eslinger MR, et al.
See legend for normal protein.
Implicated in
Oncogenesis
TACC3 is located close to the MMSET gene that is
rearranged in t(4;14) translocation (Still et al., 1999).
This rearrangement upregulates the TACC3 gene
(Stewart et al., 2004).
Ovarian cancer
Prognosis
Overexpression of TACC3 is associated with
chemoresistance in ovarian tumors (L'Esperance et al.,
2006).
Oncogenesis
Total cellular expression or nuclear localization lost in
ovarian cancer (Lauffart et al., 2005).
Thyroid cancer
Prognosis
Reduction of expression associated with increased
malignancy in cell line models (Ulisse et al., 2007).
Oncogenesis
Analysis of differentiated thyroid cancers indicates that
TACC3 mRNA levels were either upregulated (44%)
or downregulated (56%) in tumors, in some cases
correlation was observed between TACC3 and AuroraA kinase (Ulisse et al., 2007). However protein analysis
was not reported.
Non-small cell lung cancer
Prognosis
High TACC3 expression is an independent prognostic
indicator associated with significantly shorter median
survival time. TACC3 expression was correlated with
p53 expression and poor prognosis (Jung et al., 2006).
Oncogenesis
A high level of TACC3 expression was observed in
14.8% of cases of non small cell lung cancer,
predominantly of the squamous cell carcinoma type
(Jung et al., 2006).
Breakpoints
Note
Rearrangements of the human TACC3 gene have not
been described. However, translocation breakpoints in
the WHSC1 gene, associated with multiple myeloma
upregulate the intact TACC3 promoter (Stewart et al.,
2004). Tacc3 in the mouse genome is a site of proviral
integration of MoMuLV transmitted via milk from
infected mothers. This leads to upregulation of the gene
and leads to the development of lymphomas
(Chakraborty et al., 2008).
Breast cancer
Prognosis
Loss of TACC3 is observed as a predictor of poor
prognosis in breast cancer (Conte et al., 2002).
Oncogenesis
TACC3 protein downregulated in breast cancer (Conte
et al., 2002).
References
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Genomics. 1999 Jun 1;58(2):165-70
Prognosis
TACC3 overexpression correlates with the t(4;14)
translocation that is associated with poor prognosis
(Stewart et al., 2004).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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Gergely F, Karlsson C, Still I, Cowell J, Kilmartin J, Raff JW.
The TACC domain identifies a family of centrosomal proteins
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Kinoshita K, Noetzel TL, Pelletier L, Mechtler K, Drechsel DN,
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Maro B, Verlhac MH. Meiotic regulation of TPX2 protein levels
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Eslinger MR, Lauffart B, Still IH. TACC3 (transforming, acidic
coiled-coil containing protein 3). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(3):305-310.
Dephoure N, Zhou C, Villén J, Beausoleil SA, Bakalarski CE,
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
TP53INP1 (tumor protein p53 inducible nuclear
protein 1)
Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti
INSERM U.624, Parc Scientifique de Luminy, Case 915, 13288 Marseille Cedex 9, France (MS, AC, JI,
ND)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TP53INP1ID42672ch8q22.html
DOI: 10.4267/2042/44717
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
In mouse: TP53INP1 is expressed in thymus, spleen
and bone marrow. It is also expressed at low levels in
heart, stomach, liver, intestine, testis, kidney and
pancreas. TP53INP1 expression is highly induced
during the acute phase of mouse experimental
pancreatitis (caerulein induced).
In cells lines: TP53INP1 is transcriptionally induced in
response to stress in a p53-dependent and independent
manner. Examples: in mouse fibroblast, it is induced
upon adriamycin, methyl-methane sulfonate, ethanol,
H2O2, UV exposure and heat shock treatment; in
neuronal cells by copper treatment; in pancreatic cancer
cell lines by gemcitabine; in pro-B cells by IL-3
deprivation or treatement with staurosporine, cisplatin,
campto-thecin, methotrexate and paclitaxel; in mouse
embryonic fibroblast (MEF), human fibroblasts and
MCF7 by gamma irradiation; in melanoma cells by UV
mimetic compound (4NQ).
TP53INP1 expression is regulated by different
transcriptional regulators: p53, E2F1, p73 (in p53-/cells), myc (in neuroblastoma cell lines) and PLZF (in
hematopoietic cell lines).
Other names: SIP; TEAP; p53DINP1; TP53INP1A;
TP53INP1B; TP53DINP1
HGNC (Hugo): TP53INP1
Location: 8q22.1
DNA/RNA
Description
Gene is ~24 kb, with 5 exons.
Transcription
Alternative splicing: 2 transcripts: TP53INP1alpha
(exons 1, 2, 3, 4 and 5 with a stop codon in the fourth
exon) and TP53INP1beta (exons 1, 2, 3 and 5 with a
stop codon in the fifth exon).
Protein
Description
2 isoforms: TP53INP1alpha, 18 kDa (164 amino acids)
and TP53INP1beta, 27 kDa (240 amino acids). Both
isoforms contain a PEST domain (sequence rich in
proline, glutamic acid, serine and threonine between
amino acids 26 and 62 found in proteins with half-lives
of less than 2 h).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Localisation
Nuclear when over-expressed and in PML-bodies
(Promyelocytic leukemia protein) upon PML-IV overexpression.
311
TP53INP1 (tumor protein p53 inducible nuclear protein 1)
Seux M, et al.
Green boxes: exons, black lines: introns, alternative splicing for TP53INP1beta in black and TP53INP1alpha in red.
Function
Disease
Mainly in female (only 1% in male). Genetic disorders
known: loss of HER2 and ER expression, mutations in
p53 and BRCA1.
Prognosis
Mortality rate: 25%.
TP53INP1 is a tumor suppressor gene induced with
different stress conditions. TP53INP1 overexpres-sion
leads to cell cycle arrest (G1 phase) and p53-dependent
or independent apoptosis. TP53INP1 interacts with p53
and two kinases (HIPK2, and PKCd). These kinases
phosphorylate p53 on serine 46 modifying the p53
activity. TP53INP1 can modulate the p53 and p73
transcriptional activity to potentiate pro-apoptotic
pathways. Colitis and colitis-associated cancer are
exacerbated in mice deficient for TP53INP1.
Gastric cancer
Note
TP53INP1 expression is lost during cancer
development. The decreased expression of TP53INP1
protein may reflect the malignant grade of gastric
cancer.
Disease
10% are familial. Mutations in APC, p53, Bcl-2.
Prognosis
The 5-year survival after surgical resection is 30-50%
for patients with stage II and 10-25% for patients with
stage III.
Homology
TP53INP1 is conserved between species (from fly to
human). In vertebrates, one paralog has been identified,
TP53INP2 localized on chromosome 20q11.2.
TP53INP2 is involved in autophagy.
Mutations
Note
No mutation identified.
Anaplastic carcinoma of the thyroid
(ATC)
Implicated in
Note
TP53INP1 is overexpressed in anaplastic thyroid
carcinoma.
Disease
ATC is less than 2% of total thyroid cancer but
represents 40% of death by thyroid cancer. It is a very
aggressive cancer with early dissemination.
Prognosis
5-year survival rate is less than 10%.
Pancreatic Adenocarcinoma
Note
TP53INP1 is lost early during pancreatic cancer
progression (from the neoplasia stages PanIN2). This
downregulation seems to be important for tumour
development. TP53INP1 expression is down regulated
by the oncogenic micro-RNA miR-155 during
pancreatic cancer progression.
Disease
Sporadic cancer, very aggressive, epigenetic disease
with known mutations/deletions of p53, K-Ras,
SMAD4, p16, BRCA2, EGFR and HER2.
Prognosis
Very bad, with only 20% of patients reaching two years
of survival, and 3% after 5 years.
References
Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya
Y, Monden M, Nakamura Y. p53DINP1, a p53-inducible gene,
regulates p53-dependent apoptosis. Mol Cell. 2001 Jul;8(1):8594
Nowak J, Tomasini R, Mattei MG, Azizi Samir LA, Dagorn JC,
Dusetti N, Iovanna JL, Pébusque MJ. Assignment of tumor
protein p53 induced nuclear protein 1 (TP53INP1) gene to
human chromosome band 8q22 by in situ hybridization.
Cytogenet Genome Res. 2002;97(1-2):140E
Breast cancer
Note
TP53INP1 expression is lost during breast cancer
development.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Tomasini R, Samir AA, Pebusque MJ, Calvo EL, Totaro S,
Dagorn JC, Dusetti NJ, Iovanna JL. P53-dependent expression
312
TP53INP1 (tumor protein p53 inducible nuclear protein 1)
Seux M, et al.
of the stress-induced protein (SIP). Eur J Cell Biol. 2002
May;81(5):294-301
genes in primary human fibroblasts. Int J Radiat Oncol Biol
Phys. 2006 Dec 1;66(5):1506-14
Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B,
Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ.
TP53INP1s and homeodomain-interacting protein kinase-2
(HIPK2) are partners in regulating p53 activity. J Biol Chem.
2003 Sep 26;278(39):37722-9
Bell E, Lunec J, Tweddle DA. Cell cycle regulation targets of
MYCN identified by gene expression microarrays. Cell Cycle.
2007 May 15;6(10):1249-56
Bernardo MV, Yelo E, Gimeno L, Campillo JA, Parrado A.
Identification of apoptosis-related PLZF target genes. Biochem
Biophys Res Commun. 2007 Jul 27;359(2):317-22
Hershko T, Chaussepied M, Oren M, Ginsberg D. Novel link
between E2F and p53: proapoptotic cofactors of p53 are
transcriptionally upregulated by E2F. Cell Death Differ. 2005
Apr;12(4):377-83
Gironella M, Seux M, Xie MJ, Cano C, Tomasini R, Gommeaux
J, Garcia S, Nowak J, Yeung ML, Jeang KT, Chaix A, Fazli L,
Motoo Y, Wang Q, Rocchi P, Russo A, Gleave M, Dagorn JC,
Iovanna JL, Carrier A, Pébusque MJ, Dusetti NJ. Tumor
protein 53-induced nuclear protein 1 expression is repressed
by miR-155, and its restoration inhibits pancreatic tumor
development. Proc Natl Acad Sci U S A. 2007 Oct
9;104(41):16170-5
Tomasini R, Seux M, Nowak J, Bontemps C, Carrier A, Dagorn
JC, Pébusque MJ, Iovanna JL, Dusetti NJ. TP53INP1 is a
novel p73 target gene that induces cell cycle arrest and cell
death by modulating p73 transcriptional activity. Oncogene.
2005 Dec 8;24(55):8093-104
Vanlandingham JW, Tassabehji NM, Somers RC, Levenson
CW. Expression profiling of p53-target genes in coppermediated
neuronal
apoptosis.
Neuromolecular
Med.
2005;7(4):311-24
Gommeaux J, Cano C, Garcia S, Gironella M, Pietri S, Culcasi
M, Pébusque MJ, Malissen B, Dusetti N, Iovanna J, Carrier A.
Colitis and colitis-associated cancer are exacerbated in mice
deficient for tumor protein 53-induced nuclear protein 1. Mol
Cell Biol. 2007 Mar;27(6):2215-28
Ito Y, Motoo Y, Yoshida H, Iovanna JL, Nakamura Y, Kuma K,
Miyauchi A. High level of tumour protein p53-induced nuclear
protein 1 (TP53INP1) expression in anaplastic carcinoma of
the thyroid. Pathology. 2006 Dec;38(6):545-7
Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M,
Barelier S, Vasseur S, Spoto RP, Pébusque MJ, Dusetti NJ,
Iovanna JL, Carrier A. Tumor protein 53-induced nuclear
protein 1 is a major mediator of p53 antioxidant function.
Cancer Res. 2009 Jan 1;69(1):219-26
Ito Y, Motoo Y, Yoshida H, Iovanna JL, Takamura Y, Miya A,
Kuma K, Miyauchi A. Decreased expression of tumor protein
p53-induced nuclear protein 1 (TP53INP1) in breast
carcinoma. Anticancer Res. 2006 Nov-Dec;26(6B):4391-5
Nowak J, Archange C, Tardivel-Lacombe J, Pontarotti P,
Pébusque MJ, Vaccaro MI, Velasco G, Dagorn JC, Iovanna JL.
The TP53INP2 protein is required for autophagy in mammalian
cells. Mol Biol Cell. 2009 Feb;20(3):870-81
Jiang PH, Motoo Y, Garcia S, Iovanna JL, Pébusque MJ,
Sawabu N. Down-expression of tumor protein p53-induced
nuclear protein 1 in human gastric cancer. World J
Gastroenterol. 2006 Feb 7;12(5):691-6
Nowak J, Iovanna JL. TP53INP2 is the new guest at the table
of self-eating. Autophagy. 2009 Apr;5(3):383-4
Jiang PH, Motoo Y, Sawabu N, Minamoto T. Effect of
gemcitabine on the expression of apoptosis-related genes in
human pancreatic cancer cells. World J Gastroenterol. 2006
Mar 14;12(10):1597-602
This article should be referenced as such:
Seux M, Carrier A, Iovanna J, Dusetti N. TP53INP1 (tumor
protein p53 inducible nuclear protein 1). Atlas Genet Cytogenet
Oncol Haematol. 2010; 14(3):311-313.
Kis E, Szatmári T, Keszei M, Farkas R, Esik O, Lumniczky K,
Falus A, Sáfrány G. Microarray analysis of radiation response
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
313
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
del(5q) in myeloid neoplasms
Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke
FACMG, Cytogenetics Laboratory, Mayo Clinic, Rochester, Minnesota, USA (KK, RPK, DLV)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del5qID1092.html
DOI: 10.4267/2042/44718
This article is an update of:
Charrin C. del(5q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol 1998;2(3):88-90
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note
Interstitial del(5q) was first reported as a type of refractory anemia with characteristic clinical features; female
predominance (unlike other MDS), macrocytosis, erythroid hypoplasia, frequent thrombocytosis and
dysmegakaryopoiesis. It is one of the most common structural rearrangements in MDS (10%), seen as an isolated
abnormality or with additional karyotypic anomalies. It is also observed in AML, with important prognostic
significance.
del(5q) G-banding (top) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman Center (1 and
5 from the left), Kazunori Kanehira, Rhett P. Ketterling, Daniel L. Van Dyke (2, 4, 6, and 7), and Jean-Luc Lai (3); R-banding (bottom),
Courtesy Christiane Charrin (1 and 3), Editor (2).
syndrome as a specific type of MDS, restricting
diagnosis to the cases with isolated interstitial del(5q),
without excess blasts in the bone marrow (<5%). It also
defined a new category, therapy-related MDS/AML,
excluding cases with a history of previous
chemotherapy from 5q- syndrome MDS.
Clinics and pathology
Disease
5q- syndrome
Note
The World Health Organization (WHO) defined the 5q-
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
314
del(5q) in myeloid neoplasms
Kanehira K, et al.
Clinics
Cytogenetics
As described above, cases of MDS with isolated
del(5q) show female predominance (M:F=1:1.5-4),
anemia, macrocytosis, normal or moderately decreased
WBC, normal or moderately decreased platelet count,
and dysmegakaryopoiesis.
Cytogenetics morphological
The most commonly observed interstitial deletions are
del(5)(q13q31), del(5)(q13q33), and del(5)(q22q33),
forming a commonly deleted region (CDR) at 5q31q32.
Treatment
Cytogenetics molecular
Supportive care including RBC transfusion for anemia
is the mainstay of treatment. It is not infrequent that
transfusions are needed for years, causing iron
overload, and increasing the risk of blood-borne
infections. Anemia of 5q- syndrome does not respond
well to erythropoietin. Leanalidomide, a Thalidomide
derivative, has been investigated for treatment of MDS
with 5q-. Lenalidomide has immunomodulatory
properties, including the suppression of proinflammatory cytokine production by monocytes,
enhancement of T-cell and NK-cell activation, and
inhibition of angiogenesis. In Phase II trials in
transfusion-dependent MDS with 5q-, 168 patients
were enrolled, of whom 76% had isolated 5q- and 29%
had the 5q- syndrome. Transfusion independence was
obtained in 67%. A complete cytogenetic response was
achieved in 45% of patients. Cytogenetic response rate
was not significantly different in isolated del(5q),
del(5q) + 1 and del(5q) + >1 additional chromosome
abnormalities. Although the results of lenalidomide
treatment seem promising, it is not yet clear if the
treatment will affect the natural disease course and
prolongs survival.
The CDR is the approximately 1.5 Mb interval between
D5S413 and GLRA1 gene, containing around 40 genes.
No cases of 5q- syndrome have been reported to have
biallelic deletion within the CDR, and no point
mutations have been found in the genes in the region.
Recently, it is suggested that haploinsufficienty (a gene
dosage effect) of one or more of the genes mapping to
the CDR is the pathogenetic basis of the 5q- syndrome.
Ebert et al. demonstrated that impaired function of the
ribosomal subunit protein RPS14 recapitulated the
characteristic phenotype of the 5q- syndrome, a severe
decrease in the production of erythroid cells with
relative preservation of megakaryocytic cells, in normal
CD34+ human hematopoietic progenitor cells. In
addition, forced expression of RPS14 rescued the
disease phenotype in patient-derived bone marrow
cells.
Germline heterozygous mutations for two other
ribosomal proteins, RPS19 and RPS24, have recently
been described in the congenital disorder known as
Diamond-Blackfan anemia. The conge-nital anemia is
characterized by sever anemia, macrocytosis, relative
preservation of the platelet and neutrophil count,
erythroid hypoplasia in the bone marrow and an
increased risk of leukemia. The erythroid specificity of
5q- syndrome and Diamond-Blackfan anemia in
ribosomal expression is noteworthy.
Prognosis
The impact of lenalidomide on the prognosis of MDS
patients with 5q- is unknown at this point. Progression
to AML is rare (10%). With the supportive therapy, the
prognosis of 5q- syndrome is favorable, with reported
median survival ranging from 53 to 146 months. MDS
patients with 5q- plus one additional chromosome
abnormality seem to have significantly shorter survival
(with exception of loss of the Y chromosome). MDS
with 5q- as part of a complex karyotype (3 or more
abnormalities) have an unfavorable prognosis.
Additional anomalies
By definition, an interstitial deletion of 5q must be the
sole abnormality for 5q- syndrome. However, 5q
deletion can be seen with other accompanying
abnormalities. Review of the recent Mayo Clinic cases
shows that major abnormalities include -7, +8, -20,
20q-, -13/13q-, and abnormalities in 12p, in the
descending order.
Disease
AML (Acute Myeloid Leukemia).
Clinics
References
Deletion of 5q can be observed in both de novo and
therapy related AML. It is also seen as monosomy 5. In
AML, 5q deletion is usually associated with a complex
karyotype.
Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux
JL, Sokal G. Distinct haematological disorder with deletion of
long arm of no. 5 chromosome. Nature. 1974 Oct
4;251(5474):437-8
Prognosis
Pedersen B, Jensen IM. Clinical and prognostic implications of
chromosome 5q deletions: 96 high resolution studied patients.
Leukemia. 1991 Jul;5(7):566-73
Prognosis of AML with 5q-/-5 is generally unfavorable,
associated with rapid disease progression and poor
outcome and survival, especially when it is seen as a
part of complex karyotype.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Rubin CM, Arthur DC, Woods WG, Lange BJ, Nowell PC,
Rowley JD, Nachman J, Bostrom B, Baum ES, Suarez CR.
Therapy-related myelodysplastic syndrome and acute myeloid
leukemia in children: correlation between chromosomal
abnormalities and prior therapy. Blood. 1991 Dec
1;78(11):2982-8
315
del(5q) in myeloid neoplasms
Kanehira K, et al.
Neuman WL, Rubin CM, Rios RB, Larson RA, Le Beau MM,
Rowley JD, Vardiman JW, Schwartz JL, Farber RA.
Chromosomal loss and deletion are the most common
mechanisms for loss of heterozygosity from chromosomes 5
and 7 in malignant myeloid disorders. Blood. 1992 Mar
15;79(6):1501-10
Bernasconi P, Boni M, Cavigliano PM, Calatroni S, Giardini I,
Rocca B, Zappatore R, Dambruoso I, Caresana M. Clinical
relevance of cytogenetics in myelodysplastic syndromes. Ann
N Y Acad Sci. 2006 Nov;1089:395-410
Cherian S, Bagg A. The genetics of the myelodysplastic
syndromes: classical cytogenetics and recent molecular
insights. Hematology. 2006 Feb;11(1):1-13
Baranger L, Szapiro N, Gardais J, Hillion J, Derre J, Francois
S, Blanchet O, Boasson M, Berger R. Translocation
t(5;12)(q31-q33;p12-p13):
a
non-random
translocation
associated with a myeloid disorder with eosinophilia. Br J
Haematol. 1994 Oct;88(2):343-7
Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone
RM, Ritz J, Alyea EP, Antin JH, Soiffer RJ. Impact of
cytogenetics on outcome of de novo and therapy-related AML
and MDS after allogeneic transplantation. Biol Blood Marrow
Transplant. 2007 Jun;13(6):655-64
Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome. Blood.
1994 Nov 15;84(10):3253-60
in
Haase D. Cytogenetic features in myelodysplastic syndromes.
Ann Hematol. 2008 Jul;87(7):515-26
Fenaux P. Syndromes myelodysplasiques et deletion 5q.
Hematologie. 1995; 1: 35-43.
Kelaidi C, Eclache V, Fenaux P. The role of lenalidomide in the
management of myelodysplasia with del 5q. Br J Haematol.
2008 Feb;140(3):267-78
Boultwood J, Fidler C. Chromosomal deletions
myelodysplasia. Leuk Lymphoma. 1995 Mar;17(1-2):71-8
Van den Berghe H, Michaux L. 5q-, twenty-five years later: a
synopsis. Cancer Genet Cytogenet. 1997 Mar;94(1):1-7
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein
H, Thiele J, Vardiman JW.. WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues. WHO Classification of
Tumours of Haematopoietic and Lymphoid Tissues, 4th
Edition; 2008;102.
Giagounidis AA, Germing U, Wainscoat JS, Boultwood J, Aul
C. The 5q- syndrome. Hematology. 2004 Aug;9(4):271-7
Nishino HT, Chang CC. Myelodysplastic syndromes:
clinicopathologic features, pathobiology, and molecular
pathogenesis. Arch Pathol Lab Med. 2005 Oct;129(10):1299310
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
This article should be referenced as such:
Kanehira K, Ketterling RP, Van Dyke DL. del(5q) in myeloid
neoplasms. Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):314-316.
316
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(11;11)(q13;q23)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1111q13q23ID1541.html
DOI: 10.4267/2042/44719
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Epidemiology
Cytogenetics morphological
The involvement of MLL in 11q23 and ARHGEF17 in
11q13 was ascertained in only 1 case (Teuffel et al.,
2005). It was an unusual case of treatment-related MLL
rearrangement in the absence of leukemia.
The t(11;11) was apparently the sole anomaly in 3 of
the 4 cases; a complex karyotype with del(5q), a
marker chromosome, and other anomalies was found in
the case reported by Mackinnon and Campbell, 2007.
Clinics
Genes involved and proteins
The case reported by Teuffel et al. (2005), was a fiveyear-old girl, who experienced an acute myeloid
leukemia (AML) with a variant t(8;21) and achieved
remission under treatment. Four years later, a follow-up
control of her karyotype revealed a t(11;11)(q13;q23),
in the absence of any sign of leukemia in the bone
marrow, over a period of 30 months following the
discover of the t(11;11).
Other cases of t(11;11)(q13;q23) were:
A 13-year-old girl, who have had a M4eo AML with
inv(16)(p13q22).
Eleven
month
later,
a
t(11;11)(q13;q23) was found, but bone marrow
remained normal; however, an overt M5b AML was
diagnosed 6 months later (Leblanc et al., 1994). This
case resembles the case of Teuffel.
There was also the case of a 69-year-old male patient
with a primary M4 AML, who died 5 months after
diagnosis, and an AML (not classified) female patient
(Testa et al., 1985; Mackinnon and Campbell, 2007).
ARHGEF17
Location
11q13
Protein
Guanine nucleotide exchange factor (GEF) for RhoA
GTPases. Involved in transduction of various signals
into downstream signaling cascades.
MLL
Location
11q23
DNA/RNA
36 exons, multiple transcripts 13-15 kb.
Protein
3969 amino acids; 431 kDa; contains two DNA binding
motifs (a AT hook and a CXXC domain), a DNA
methyl transferase motif, a bromodomain. MLL is
cleaved by taspase 1 into 2 proteins before entering the
nucleus, called MLL-N and MLL-C.
The FYRN and FRYC domains of native MLL
associate MLL-N and MLL-C in a stable complex; they
form a multiprotein complex with transcription factor
TFIID. MLL is a transcriptional regulatory factor. MLL
can be associated with more than 30 proteins, including
Cytology
In the case reported by Teuffel, the MLL-ARHGEF17
was only seen in the myeloid lineage. The myeloid
differentiation was not perturbed by the presence of the
chimeric protein, and normal mature myeloid cells
carrying the chimeric protein were found in normal
amounts.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
317
t(11;11)(q13;q23)
Huret JL
the core components of the SWI/SNF chromatin
remodeling complex and the transcription complex
TFIID. MLL binds pro-motors of HOX genes through
acetylation and methylation of histones. MLL is a
major regulator of hematopoesis and embryonic
development.
References
Testa JR, Misawa S, Oguma N, Van Sloten K, Wiernik PH.
Chromosomal alterations in acute leukemia patients studied
with improved culture methods. Cancer Res. 1985
Jan;45(1):430-4
Leblanc T, Hillion J, Derré J, Le Coniat M, Baruchel A, Daniel
MT, Berger R. Translocation t(11;11)(q13;q23) and HRX gene
rearrangement associated with therapy-related leukemia in a
child previously treated with VP16. Leukemia. 1994
Oct;8(10):1646-8
Result of the chromosomal
anomaly
Hybrid gene
Teuffel O, Betts DR, Thali M, Eberle D, Meyer C, Schneider B,
Marschalek R, Trakhtenbrot L, Amariglio N, Niggli FK, Schäfer
BW. Clonal expansion of a new MLL rearrangement in the
absence of leukemia. Blood. 2005 May 15;105(10):4151-2
Description
The fusion between MLL and ARHGEF17 occurred in
introns 12 and 1 respectively.
Mackinnon RN, Campbell LJ. Dicentric chromosomes and
20q11.2 amplification in MDS/AML with apparent monosomy
20. Cytogenet Genome Res. 2007;119(3-4):211-20
This article should be referenced as such:
Huret JL. t(11;11)(q13;q23). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(3):317-318.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
318
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(11;19)(q23;p13.3) MLL/ACER1
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1119q23p13ID1540.html
DOI: 10.4267/2042/44720
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
ACER1
Clinics and pathology
Location
19p13.3
Protein
ACER1 is the alkaline ceramidase 1. Ceramidases
catalyze hydrolysis of ceramide to generate sphingosine
(SPH), which is phosphorylated to form sphingosine-1phosphate (S1P). Ceramide, SPH, and S1P are
bioactive lipids that mediate cell proliferation,
differentiation, apoptosis, adhesion and migration (Mao
and Obeid, 2008).
Disease
Acute lymphocytic leukemia (ALL)
Epidemiology
Only one case to date, a case of congenital leukemia
(Lo Nigro et al., 2002).
Genes involved and proteins
MLL
Location
11q23
DNA/RNA
36 exons, multiple transcripts 13-15 kb.
Protein
3969 amino acids; 431 kDa; contains two DNA binding
motifs (a AT hook and a CXXC domain), a DNA
methyl transferase motif, a bromodomain. MLL is
cleaved by taspase 1 into 2 proteins before entering the
nucleus, called MLL-N and MLL-C. The FYRN and
FRYC domains of native MLL associate MLL-N and
MLL-C in a stable complex; they form a multiprotein
complex with transcription factor TFIID. MLL is a
transcriptional regulatory factor. MLL can be
associated with more than 30 proteins, including the
core components of the SWI/SNF chromatin
remodeling complex and the transcription complex
TFIID. MLL binds pro-motors of HOX genes through
acetylation and methylation of histones. MLL is a
major regulator of hematopoesis and embryonic
development.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Result of the chromosomal
anomaly
Hybrid gene
Description
5' MLL - 3' ACER1; fusion of MLL intron 8 to
ACER1.
References
Lo Nigro L, Slater DJ, Rappaport EF, Biondi A, Maude S,
Megnigal MD, Bungaro S, Schiliro G, Felix CA.. Two partner
genes of MLL and additional heterogeneity in t(11;19)(q23;p13)
translocations. Blood 2002; 2080 p531a.
Mao C, Obeid LM. Ceramidases: regulators of cellular
responses mediated by ceramide, sphingosine, and
sphingosine-1-phosphate. Biochim Biophys Acta. 2008
Sep;1781(9):424-34
This article should be referenced as such:
Huret JL. t(11;19)(q23;p13.3) MLL/ACER1. Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(3):319.
319
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(2;5)(p21;q33)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0205p21q33ID1511.html
DOI: 10.4267/2042/44721
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
domains, a transmembrane domain, and an intracellular
part with a tyrosine kinase domain (made of two
tyrosine kinase subdomains) for transduction of the
signal. Receptor tyrosine kinase; receptor for PDGFB
and PDGFD (Bergsten et al., 2001); forms
homodimers, or heterodimer with PDGFRA; upon
dimerization,
subsequent
activa-tion
by
autophosphorylation of the tyrosine kinase intracellular
domains occurs.
Clinics and pathology
Disease
Atypical myeloproliferative disease with eosino-philia
Epidemiology
One case to date, a 73-year-old female patient
(Gallagher et al., 2008).
Prognosis
The patient was alive and well after 3 years of therapy
with imatinib.
Result of the chromosomal
anomaly
Cytogenetics
Fusion protein
Cytogenetics morphological
Description
Constitutive activation of the PDGFRB tyrosine kinase
domain.
The t(2;5) was the sole anomaly.
Genes involved and proteins
References
SPTBN1
Winkelmann JC, Forget BG. Erythroid and nonerythroid
spectrins. Blood. 1993 Jun 15;81(12):3173-85
Location
2p16.2 is the exact location
Protein
SPTBN1 (spectrin beta1 non erythrocytic), also called
beta-fodrin, is a cytoskeleton protein. Forms dimers
with alpha-fodrin (SPTAN1, 9q34), which selfassociates head-to-head into tetramers. Mem-brane
skeleton protein associated with ion channels and
pumps (Winkelmann and Forget, 1993); Stabilizes cell
surface membranes; role in mitotic spindles assembly
(Bennett and Baines, 2001).
Bennett V, Baines AJ. Spectrin and ankyrin-based pathways:
metazoan inventions for integrating cells into tissues. Physiol
Rev. 2001 Jul;81(3):1353-92
Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH,
Alitalo K, Eriksson U. PDGF-D is a specific, protease-activated
ligand for the PDGF beta-receptor. Nat Cell Biol. 2001
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Gallagher G, Horsman DE, Tsang P, Forrest DL. Fusion of
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PDGFRB
This article should be referenced as such:
Location
5q33
Protein
Comprises an extracellular part with 5 Ig-like C2 type
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Huret JL. t(2;5)(p21;q33). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(3):320.
320
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Review
Head and Neck: Ear: Endolymphatic Sac Tumor
(ELST)
Rodney C Diaz
Department of Otolaryngology-Head and Neck Surgery, University of California Davis Medical Center,
Sacramento, California 95817, USA (RCD)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Tumors/EndolymphaticSacTumID5096.html
DOI: 10.4267/2042/44722
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Clinics and pathology
Alias
Low Grade Papillary Adenocarcinoma of the
Endolymphatic Sac, Papillary Adenoma of the
Endolymphatic Sac.
Note
Endolymphatic sac tumors (ELSTs) are rare tumors of
the petrous temporal bone. Classified as mastoid
papillary tumors of unknown origin, these tumors were
synthesized into a new, distinct clinico-pathological
entity by Heffner in 1989. Initially described as a low
grade papillary adenocarcinoma, their histologic
appearance and apparent lack of metastatic potential
has since persuaded most practitioners to reclassify
them as papillary adenomas. ELSTs can arise
sporadically or in association with von Hippel-Lindau
(VHL) disease.
Disease
Classification
Etiology
Endolymphatic sac tumors are rare. As a recognized,
distinct entity, ELSTs are relatively new.
The first reported case of a tumor arising from the
endolymphatic
sac
was
discovered
during
decompression of the endolymphatic sac for presumed
unilateral Ménière's Disease in 1984.
Although benign, ELSTs can be locally destructive.
They present with hearing loss, tinnitus, facial nerve
weakness or paralysis, vertigo, and can be lethal. CT
imaging demonstrates erosion of the posterior petrous
temporal bone
with occasional intratumoral
calcification. MRI tumor signal is isointense to brain
and demonstrates gadolinium enhancement and
heterogeneous signal intensity from intratumoral
calcification and vascularity.
The synthesis of sporadic temporal bone papillary
tumors into a distinct clinicopathological entity was
proposed in 1989 by Heffner, with the anatomic origin
of these tumors being the endolymphatic sac.
Knowledge of this tumor has grown, expedited in part
by its association with VHL disease, yet many aspects
are still poorly understood.
Note
The differential diagnosis for ELSTs includes all
intrinsic temporal bone neoplasms (most commonly
paraganglioma) as well as metastatic papillary thyroid
carcinoma, metastatic renal cell carcinoma, and choroid
plexus papilloma, the latter three of which are similar
in appearance to ELSTs histologically.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
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MRI T1 weighted axial images of the brain at the level of the endolymphatic sac and internal auditory canal. The top view without
gadolinium contrast shows moderate expansion of the endolymphatic sac and duct on the right. The bottom view with gadolinium
contrast shows contrast enhancement of the endolymphatic sac on the right.
CT axial image of the temporal bones at the level of the endolymphatic sac and internal auditory canals. The vestibular aqueduct on the
right is markedly widened directly behind the internal auditory canal and vestibule, in contrast to the appearance of the vestibular
aqueduct on the left, which is thin and nondescript. The bony erosion and widening of the vestibular aqueduct on the right is highly
suggestive of a neoplastic or otherwise destructive process within the endolymphatic sac, consistent with an ELST.
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
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Initially described as a low grade papillary
adenocarcinoma, the histologic appearance and
apparent lack of metastatic potential of these tumors
has convinced some to reclassify them as benign
papillary adenomatous tumors. The high overall
survival following surgical resection, despite locally
aggressive behavior, is likely due to the underlying
benign histology of the tumor.
tumor. Large glomus tumors as well as large ELSTs
can both present as pink or purple masses encroaching
on the middle ear and external auditory canal. Glomus
tumors exhibit a characteristic "salt and pepper" tumor
appearance on MRI, but this heterogeneity in signal
reflects the vascularity of such tumors and is not
pathognomonic. The heterogeneity in signal seen in
large ELSTs - arising from hypervascularity as well as
intra-tumoral hemorrhage and/or calcification - can
often mimic glomus tumors in this respect. This is not
necessarily problematic, as management would proceed
similarly for either histologic type of tumor: preoperative embolization followed by total tumor
resection via the appropriate lateral skull base
approach.
Epidemiology
Over 175 case reports of ELSTs have now been
reported in the literature. The majority of these are
single case reports of a practice group or university.
As the majority of these case reports do not disclose the
population size of their patient base, it is difficult to
assess the true incidence of these tumors. ELSTs tend
to afflict women more than men with an overall female
to male ratio of 2:1 in a review of the literature.
Pathology
ELSTs are highly vascular and are comprised of
papillary cystic structures lined with a simple cuboidal
or columnar epithelium. Siderophages and cholesterol
clefts are seen, as are clear, vacuolated cells. Nuclear
pleomorphism is not pronounced, and mitoses are rare.
Immunohistochemistry and special staining may aid in
differentiation of papillary tumors of question-able
origin. ELSTs usually stain positive for cytokeratin,
vimentin, and epithelial membrane antigen, as well as
stain on Periodic acid-Schiff (diastase sensitive). Some
papers have also reported sensitivity to glial fibrillary
acid protein; however, most authors have had poor
tumor reactivity to glial fibrillary acid protein. Papillary
thyroid metastasis to the temporal bone may be
differentiated by positive reaction to thyroglobulin
immunohisto-chemistry.
Transthyretin has been shown to exhibit differential
expression in choroid plexus papillomas with little to
no expression in ELSTs.
Clinics
The most common presenting complaints were aural,
with hearing loss occurring in neary every reported
patient, followed by tinnitus, aural fullness, and
imbalance. The symptoms of pulsatile tinnitus, otalgia,
otorrhea, vertigo, and facial paresis were also present in
some patients. Cranial neuropathies were also
diagnosed either at the time of presentation or
following treatment. The most commonly involved
nerve was the facial nerve, with preoperative facial
paresis or paralysis in 43% of patients. In patients with
larger tumors or in those who delayed presentation for
decades after onset of initial symptoms, multiple
cranial neuropathies were present including trigeminal,
glossopharyngeal, and vagal nerves.
From a statistical standpoint, a vascular tumor eroding
the temporal bone and cranial base is likely to be a
paraganglioma, and likely a glomus jugulare
MRI T1 weighted images of the brain, showing a very large ELST of the left temporal bone, in axial view on the left and coronal view on
the right. There has been complete erosion of the petrous temporal bone by the tumor, with significant brainstem and cerebellar
compression.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Diaz RC
Histological appearance of ELST. HE stain, low power magnification, demonstrating the characteristic papillary cystic architecture of
these tumors.
conservation procedures while 68% underwent hearing
ablative procedures. In patients with excellent
preoperative hearing and a small ELST, such a hearing
conservation approach may be warranted. However, the
completeness of tumor resection should not be
compromised for the sake of hearing conservation. Half
of patients undergoing hearing conservation approaches
with subtotal resection followed by adjuvant radiation
therapy had regrowth of tumor.
In some tumors, total resection cannot be achieved
without risk of catastrophic loss of function or death,
and in these patients subtotal resection may be
warranted. Patients who have subtotal resection may
benefit from postoperative radiotherapy, but there still
remains a roughly 50% risk of tumor regrowth and
therefore close surveillance is warranted as re-resection
may be necessary. Stereotactic radiotherapy has shown
no increased benefit above standard fractionated
radiotherapy in survival or recurrence rates, and
Treatment
Surgical resection is the primary modality of treatement
for ELSTs. Despite the benign histologic nature of
these tumors, complete resection appears crucial for
ensuring success. Total tumor resection is clearly the
treatment of choice, as only one patient with reported
complete resection had subsequent recurrence.
Although the most common presenting symptom was
sensorineural hearing loss, many patients, particularly
those with VHL disease, present with small ELSTs and
consequently present with serviceable hearing. VHL
patients are unique in that all undergo active
surveillance and cranial imaging for hemangioblastoma
as part of their VHL disease management.
Subsequently, ELSTs in these patients are frequently
diagnosed early, with relatively little delay between
onset of audio-vestibular symptoms and identification
of tumor. This significantly affected surgical decision
making, as 32% of patients underwent hearing
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
324
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Diaz RC
subtotal resection followed by stereotactic radiotherapy
has uniformly resulted in tumor regrowth. There are no
reported cases of radiation therapy and/or stereotactic
radiotherapy used as the primary modality of treatment
for ELSTs.
hemangioblastomas,
retinal
hemangioblas-tomas,
pheochromocytomas, and cysts of the kidneys,
pancreas, and epididymis.
The gene responsible for VHL disease is a tumor
suppressor and it has been mapped to chromosome
3p25. The VHL gene product pVHL forms a multiprotein complex that contains elongin B, elongin C,
Cul-2, and Rbx1.
The pVHL complex has a role in oxygen sensing. The
VHL gene regulates vascular endothelial growth factor
VEGF, and inactivation of the gene promotes VEGF
overexpression and angiogenesis. In addition, its loss of
function mutation can increase expression of hypoxiainducible factor HIF1, stimulating angiogenesis and
tumorigenesis. In VHL disease, it is believed that
tumors arise when both an inherited germline mutation
and a loss-of-function mutation of the wild-type VHL
gene are present.
In addition, it has been shown that somatic mutations to
the VHL gene locus at 3p25/26 are detected even in
cases of sporadic ELSTs, that is, in non-VHL patients.
Genetic sequencing analysis of the 3p25 VHL gene
locus in both sporadic and VHL-associated ELSTs
demonstrates nucleotide substitution as well as
deletion/frameshift errors.
Even though temporal bone lesions were described in
patients by Lindau in 1926, the association of these
tumors with VHL disease was not made until recently.
This clinical association has been confirmed at the
molecular level with mutations in the VHL gene
identified in endolymphatic sac tumors in VHL
patients. Approximately 10% of patients with VHL
disease have ELSTs, and approximately 30% of VHL
patients with ELSTs have bilateral tumors. This
variable phenotypic expression may be a reflection of
VHL gene function secondary to the type of mutation
present.
Indeed, VHL disease has been found to have
phenotypic expression consistent within members of a
family, thus implying a singular, conserved mutation
within affected families. VHL disease is categorized
into two familial types, with type 1 being without
pheochromocytomas and type 2 being with
pheochromocytomas. There is further subclassification
of type 2 into type 2a, low risk for developing renal cell
carcinoma, and type 2b, high risk for developing renal
cell carcinoma. Clinical presentation type correlates
with genetic mutation type: type 1 families usually
have deletion or truncation mutations, whereas type 2
families usually have missense mutations.
If a family history of VHL disease exists, or if the
diagnosis of VHL disease is made in the absence of an
ELST, then early routine audiologic screening can
allow for early tumor detection and the possibility of
hearing preservation surgery should ELST develop.
Positive identification of tumor on MRI with
gadolinium is necessary prior to surgery: to date,
Evolution
There are currently no reported cases of spontaneous
metastatic dissemination of ELSTs in the literature.
Recently however, two reports have surfaced
describing metastatic disease following subtotal
resection. The first was a reported case of ELST drop
metastasis with dissemination onto the ipsilateral
cerebellar convexity beyond the original tumor site in a
patient who had undergone previous subtotal resection
and radiotherapy. A second case of drop metastasis of
ELST involved the spine, manifesting after multiple
subtotal resections and three courses of stereotactic
radiosurgery.
These seminal reports serve to illustrate the importance
of complete tumor removal on initial resection in order
to minimize both recurrence and metastatic seeding.
The oncologic principle of complete tumor extirpation
on primary resection is certainly applicable to ELSTs,
despite their benign histology and absence of
spontaneous metastasis.
Prognosis
Overall survival characteristics for all reported cases of
ELSTs are: 74% no evidence of disease, 20% alive
with disease, and 4% died of disease, for the reporting
periods.
ELSTs are histologically benign yet sometimes
destructive, highly aggressive lesions. They show
excellent response to primary surgical resection, with
or without adjuvant radiotherapy. Complete tumor
removal on initial resection is crucial. Hearing
preservation should not take precedence over complete
tumor removal, as adjuvant radiotherapy does not
ensure against tumor recurrence, which can be
devastating and lethal. In addition, drop metastases
following subtotal tumor resection have now been
reported. In patients with VHL disease, regularly
scheduled audiometry and surveillance MRI are vital to
early detection of ELSTs, which can optimize the
opportunity for hearing preservation without
compromising tumor control.
Genetics
Note
The current literature suggests that approximately one
third of all ELSTs are associated with VHL disease.
VHL disease is an autosomal dominant familial cancer
syndrome. VHL disease affects approximately 1 in
39,000 people. It encompasses a variety of neoplasia
both benign and malignant including renal cell
carcinomas, central nervous system
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
325
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Diaz RC
endolymphatic sac tumor. J Natl Cancer Inst. 1997 Jul
2;89(13):970-2
surgical exploration in VHL patients with
audiovestibular symptoms but without MRI abnormallities has not been documented and is not
recommended.
Noujaim SE, Pattekar MA, Cacciarelli A, Sanders WP, Wang
AM. Paraganglioma of the temporal bone: role of magnetic
resonance imaging versus computed tomography. Top Magn
Reson Imaging. 2000 Apr;11(2):108-22
Genes involved and proteins
Vortmeyer AO, Huang SC, Koch CA, Governale L, Dickerman
RD, McKeever PE, Oldfield EH, Zhuang Z. Somatic von
Hippel-Lindau gene mutations detected in sporadic
endolymphatic sac tumors. Cancer Res. 2000 Nov
1;60(21):5963-5
VHL
Location
3p25.3
DNA / RNA
The VHL gene is a tumor suppressor gene mapped to
chromosome 3p25/26.
Protein
The VHL gene product, pVHL, forms a multi-protein
complex that contains elongin B, elongin C, Cul-2, and
Rbx1.
Hamazaki S, Yoshida M, Yao M, Nagashima Y, Taguchi K,
Nakashima H, Okada S. Mutation of von Hippel-Lindau tumor
suppressor gene in a sporadic endolymphatic sac tumor. Hum
Pathol. 2001 Nov;32(11):1272-6
Ferreira MA, Feiz-Erfan I, Zabramski JM, Spetzler RF, Coons
SW, Preul MC. Endolymphatic sac tumor: unique features of
two cases and review of the literature. Acta Neurochir (Wien).
2002 Oct;144(10):1047-53
Megerian CA, Haynes DS, Poe DS, Choo DI, Keriakas TJ,
Glasscock ME 3rd. Hearing preservation surgery for small
endolymphatic sac tumors in patients with von Hippel-Lindau
syndrome. Otol Neurotol. 2002 May;23(3):378-87
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This article should be referenced as such:
Diaz RC. Head and Neck: Ear: Endolymphatic Sac Tumor
(ELST). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):321-326.
Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. von
Hippel-Lindau disease gene alterations associated with
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
326
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Lymphangioleiomyoma
Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss
Translational Medicine Branch, NHLBI, NIH, Building 10, Room 6D05, MSC 1590, Bethesda, Maryland
20892-1590, USA (CGG, AMTD, JM)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Tumors/LymphangioleiomyomaID5868.html
DOI: 10.4267/2042/44723
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
result from pulmonary or extrapulmonary lesions.
Pulmonary LAM is characterized by thin-walled cysts,
which are diffused throughout the lungs. Patients with
these lesions experience deterioration of lung function
that can lead to oxygen depen-dency, lung
transplantation or death. Extrapul-monary LAM
involves the axial lymphatics of the abdomen and
thorax (lymphangioleiomyomas, adenopathy), and
abdominal
organs,
especially
the
kidneys
(angiomyolipomas).
Abdomino-pelvic lymphangioleiomyomas may present
with abdominal pain as an acute abdomen, with a
neuropathy or with abdominal bloating. Thoracoabdominal
lymphadenopathy
and
lymphangioleiomyomas, along with chylothorax (Figure 1) or
ascites may suggest the presence of a malignant
lymphoproliferative disease.
Classification
Note
Lymphangioleiomyoma is a benign neoplasm of
lymphatic vessels characterized as a PEComa
(perivascular epithelioid cell tumour), involving the
proliferation of epithelioid cells, with mutations in the
tuberous sclerosis complex (TSC) genes TSC1 and
TSC2.
Clinics and pathology
Note
Lymphangioleiomyomas are commonly associated with
lymphangioleiomyomatosis (LAM), a multi-system
disorder primarily affecting women of child-bearing
age. Initial presentation of LAM may
Figure 1: Large left chylous pleural effusion (white arrow) in a patient with LAM.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
327
Lymphangioleiomyoma
Glasgow CG, et al.
Figure 2 A, B, C, D, and E. Histological characterization of extrapulmonary LAM. LAM cells form fascicles separated by lymphatic
channels (A). (HE, original magnification x 100) An example of LAM cells arranged in trabecular bundles and irregular papillary patterns
(B). (H&E, original magnification x 250) Image representing morphological heterogeneity of LAM cells; large epithelioid LAM cells
(asterik) and smaller, round to oval cells (arrows) (C). (H&E, original magnification x 1,000) Positive reactivity of LAM cells to HMB-45
(D). (immunoperoxidase with hematoxylin counterstain, original magnification x 400) Positive reactivity of LAM cells to SMMHC (E).
(original magnification x 400). (from Matsui et al., Hum Pathol. 2000 October;31(10):1242-1248).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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Lymphangioleiomyoma
Glasgow CG, et al.
leakage and intractable chylothorax and ascites.
Chylous effusions including pleural effusions are
particularly difficult to treat. Repeated thora-centeses
lead to malnutrition and may result in infectious
complications. Low fat diet with medium-chain
triglycerides and therapeutic thora-centesis should be
attempted initially. However, most patients require
pleurodesis, which may be effective if the rate of chyle
generation can be reduced. Patients should be placed on
a fat-free parenteral nutrition regimen prior to, during,
and after surgery. It is essential that good lung
expansion be obtained to ensure complete apposition of
the visceral and parietal pleura to avoid residual pleural
pockets. After a successful pleurodesis, a low fat diet
with mid-chain trigly-cerides is recommended. A
peritoneal-venous shunt may be considered for most
severe cases when the ascites is disabling and is
causing mechanical/ nutritional problems, but little
experience with this therapeutic modality in LAM is
reported. Treatment with octreotide may be considered
for those patients with disabling ascites and large
lymph-angioleiomyomata. Previous studies with
somato-statin and octreotide in other clinical settings
(e.g., traumatic damage to the lymphatics, yellow nail
syndrome) have shown a successful reduction in
chylous effusions, chyluria, ascites, and peripheral
lymphedema.
Sirolimus: The TSC1 and TSC2 genes encode
respectively, hamartin and tuberin. Although Hamartin
and tuberin may have individual functions, they are
also known to interact in a cytosolic complex.
Hamartin may play a role in the reorganization of the
actin cytoskeleton. Tuberin has roles in pathways
controlling cell growth and proliferation. It is a
negative regulator of cell cycle progression, and loss of
tuberin function shortens the G1 phase of the cell cycle.
Tuberin binds p27KIP1, a cyclin-dependent kinase
inhibitor, thereby preventing its degradation and
leading to inhibition of the cell cycle. Tuberin also
integrates signals from growth factors and energy
stores through its interaction with mTOR (mammalian
target of rapamycin). Tuberin has Rheb GAP (Ras
homolog enriched in brain GTPase-activating protein)
activity, which converts active Rheb-GTP to inactive
Rheb-GDP. Rheb regulates mTOR, a serine/threonine
kinase that phosphorylates at least two substrates: 4EBP1, allowing cap-dependent translation, and S6K1,
leading to translation of 5' TOP (terminal
oligopyrimidine
tract)-containing
RNAs.
Phosphorylation of tuberin by Akt, which is activated
by growth factors, leads to inhibition of tuberin,
resulting in cell growth and proliferation.
Phosphorylation of tuberin by AMPK (AMP-activated
kinase) activates tuberin and further promotes
inhibition of cell growth in conditions of energy
deprivation.
Etiology
LAM results from proliferation of an abnormal cell,
termed the LAM cell. LAM occurs in 30-40% of
patients with tuberous sclerosis complex, an autosomal
dominant disorder associated with mutations in the
TSC1 or TSC2 genes. Sporadic LAM is caused
presumably by cells with mutations of the TSC2 gene.
Lymphatic
involvement
(including
lymphangioleiomyomas) occurs less frequently in
patients with LAM/TSC, than in patients with sporadic
LAM.
Epidemiology
Lymphangioleiomyomas are present in about 16-21%
of patients with LAM.
Pathology
Histological examination of the cells lining the walls of
the
extrapulmonary
lesions
reveal
common
characteristics with pulmonary LAM cells, abnormal
smooth muscle-like cells with a mixture of epithelioid
and splindle-shaped morphologies. Cells react with
HMB-45, a monoclonal antibody against gp100 (a
premelanosomal marker), and with antibodies against
SMMHC, a smooth muscle-cell marker. Unlike the
nodular collections of the pulmonary LAM cells, the
extrapulmonary cells usually form fascicles or papillary
patterns. Both types of lesions contain slit-like
lymphatic channels (Figure 2A, B, C, D, and E).
Radiologic Imaging: Retroperitoneal lymphangioleiomyomas have a distinctive radiologic appearance
(Figures 3-7), and diurnal variation in size of the tumor
masses can be demonstrated by ultrasonography or
computed tomography scans (Figure 8).
Lymphangioleiomyomas are well characterized by
either ultrasonography or computed tomography
scanning, appearing as well-circumscribed lobular, thin
or thick-walled masses without evidence of necrosis or
hemorrhage. Masses greater than 3 cm in diameter are
usually cystic in appearance and many contain fluid,
presumably chyle. Lesions as large as 20 cm in
diameter have been observed. In patients with LAM,
the lesions most often occur in the retroperitoneal
region.
Treatment
There is no effective treatment for lymphangioleiomyomas. The lesions are usually asymptomatic,
however, ascites, peripheral edema, and compres-sion
of the bladder, bowel, pelvic veins and other viscera by
large lymphangioleiomyomata may cause severe
symptomatology, including pain, obstipation, urinary
frequency, and peripheral edema. Although surgery is
sometimes contemplated to ameliorate symptoms
caused by visceral compression, it is contraindicated,
as, in our experience; it may lead to persistent
lymphatic
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Lymphangioleiomyoma
Glasgow CG, et al.
Figure 3. Mediastinal lymphangioleiomyoma (white arrow), located posteriorly to the descending thoracic aorta. A: aorta.
Figure 4. Mediastinal lymphangioleiomyomas (white arrow), located posteriorly to the trachea.
Figure 5. Large retroperitoneal lymphangioleiomyoma (white arrow) surrounding the aorta and inferior vena cava. A: aorta; IVC: inferior
vena cava.
Figure 6A and B. Black arrows point to large pelvic lymphangioleiomyoma (A). A complex lymphangioleiomyoma is shown marked by
circle on panel B.
Figure 7A, B and C. Evidence of bladder and bowel compression caused by the tumors. B: bladder.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
330
Lymphangioleiomyoma
Glasgow CG, et al.
Figure 8A, B, C and D. Diurnal variation of lymphangioleiomyomas. Abdominal ultrasound shows that the size of a lymphangioleiomyoma
is greater in the evening (panel B) that in the morning (panel A). Abdominal CT scan showing also diurnal variation in tumor size from
morning (panel C) to evening (panel D).
Sirolimus, an inmmunosuppressive agent, inacti-vates
mTOR. Sirolimus has been shown to induce apoptosis
of tumors in rodents and decrease the size of renal
angiomyolipomas
in
patients
with
lymphangioleiomyomatosis or TSC. Further, sirolimus was
effective in decreasing the size of chylous effusions and
lymphangioleiomyomas in one patient with LAM and
improved chylous effusions in another patient who
underwent lung trans-plantation.
with LAM, is correlated with more severe lung disease
assessed by computed tomography scans.
Genes involved and proteins
Note
Serum levels of VEGF-D, a lymphangiogenic growth
factor, are higher in patients with LAM than those in
healthy volunteers. In addition, serum levels of VEGFD
in
patients
with
LAM
who
have
lymphangioleiomyomas and adenopathy are higher
than in patients without lymphangioleiomyomas. LAM
lung nodules demonstrate immunoreactivity for VEGFD. Because of these findings and reported observations
of LAM cell clusters in lymphatic channels, it has been
hypothesized that LAM-associated lymphangiogenesis,
driven by VEGF-D, may account for the dissemination
of LAM cells through the shedding of LAM cell
clusters into the lymphatic system.
Evolution
Lymphangioleiomyomas are thought to occur due to
the proliferation of LAM cells in lymphatic vessels,
causing obstruction and dilatation of the vessels leading
to collection of chylous material in cyst-like structures.
The cysts, when overdistended, may rupture resulting
in chylous ascites. Lymphangioleiomyomas can exhibit
diurnal variation, (visualized by CT or sonography)
with lesions increasing in size during the day. This
phenomenon can be an aid in a differential diagnosis of
a probable lymphangioleiomyoma with thick walls and
no fluid, from other mass lesions such as a lymphoma
or a sarcoma.
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