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Volume 18 - Number 9
September 2014
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with
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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, and
also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in
Medicine and in Sciences.
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Genetics, Department of Medical Information,
University Hospital
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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
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© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with
the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific
Research (CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Editor
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee
Alessandro Beghini
Anne von Bergh
Judith Bovée
Vasantha Brito-Babapulle
Charles Buys
Anne Marie Capodano
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Fredrik Mertens
Konstantin Miller
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Elizabeth Petty
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Mariano Rocchi
Alain Sarasin
Albert Schinzel
Clelia Storlazzi
Sabine Strehl
Nancy Uhrhammer
Dan Van Dyke
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Franck Viguié
José Luis Vizmanos
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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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
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
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
Leukaemia Section
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Volume 18, Number 9, September 2014
Table of contents
Gene Section
AFAP1L2 (actin filament associated protein 1-like 2)
Xiaohui Bai, Serisha Moodley, Hae-Ra Cho, Mingyao Liu
628
ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Xiaoyu Tang, Dorothy M Morré, D James Morré
632
FABP7 (fatty acid binding protein 7, brain)
Roseline Godbout, Ho-Yin Poon, Rong-Zong Liu
638
GSTA1 (glutathione S-transferase alpha 1)
Ana Savic-Radojevic, Tanja Radic
645
MOAP1 (Modulator Of Apoptosis 1)
Gamze Ayaz, Mesut Muyan
650
PHLDA1 (pleckstrin homology-like domain, family A, member 1)
Maria Aparecida Nagai
652
ADAMTS15 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 15)
Santiago Cal, Alvaro J Obaya
655
ADRB2 (adrenoceptor beta 2, surface)
Denise Tostes Oliveira, Diego Mauricio Bravo-Calderón
659
IRF4 (interferon regulatory factor 4)
Vipul Shukla, Runqing Lu
663
PLCG1 (Phospholipase C, Gamma 1)
Rebeca Manso
668
SLC1A5 (solute carrier family 1 (neutral amino acid transporter), member 5)
Cesare Indiveri, Lorena Pochini, Michele Galluccio, Mariafrancesca Scalise
673
USB1 (U6 snRNA biogenesis 1)
Elisa Adele Colombo
678
Leukaemia Section
t(9;15)(p13;q24) PAX5/PML
Jean-Loup Huret
682
t(1;9)(p13;p12) PAX5/HIPK1
Jean-Loup Huret
685
Solid Tumour Section
Lung: t(6;12)(q22;q14.1) LRIG3/ROS1 in lung adenocarcinoma
Kana Sakamoto, Yuki Togashi, Kengo Takeuchi
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
688
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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INIST-CNRS
Deep Insight Section
The tumour suppressor function of the scaffolding protein spinophilin
Denis Sarrouilhe, Véronique Ladeveze
691
Case Report Section
Translocation t(5;6)(q33-34;q23) in an acute myelomonocytic leukemia patient
Adriana Zamecnikova, Soad Al Bahar, Ramesh Pandita
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
701
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Review
AFAP1L2 (actin filament associated protein 1like 2)
Xiaohui Bai, Serisha Moodley, Hae-Ra Cho, Mingyao Liu
Latner Thoracic Surgery Research Laboratoires, University Health Network, Toronto General
Research Institute, University of Toronto, Toronto, Ontario, Canada (XB, SM, HRC, ML)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/AFAP1L2ID52197ch10q25.html
DOI: 10.4267/2042/54026
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Identity
Review on AFAP1L2, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Other names: KIAA1914, XB130
HGNC (Hugo): AFAP1L2
Location: 10q25.3
Figure 1. XB130 chromosomal location and neighbour genes. A. xb130 gene is located on chromosome 10, at 10q25.3 by
fluorescence in situ hybridization (FISH). B. Diagram of xb130 neighbour genes between 115939029 and 116450393.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
628
AFAP1L2 (actin filament associated protein 1-like 2)
Bai X, et al.
Figure 2. XB130 functional domains and motifs. Human XB130 has 818 amino acids. It contains the following motif/domains:
proline-rich region: residues 98-107; tyrosine phosphorylation motif: residues 54-57, 124-127; 148-151; 457-460; PH domain:
residues 175-272; 353-445; coiled-coil region: residues 652-749.
approximately 130 kDa by western blotting (Xu et
al., 2007). As an adaptor protein, XB130 has no
enzymatic domains or activity. Sequence structure
analysis has revealed 23 putative tyrosine
phosphorylation
sites
and
27
putative
phosphorylation sites for serine/threonine kinases
(Xu et al., 2007). The N-terminal of XB130
contains a proline rich, SH3 domain binding motif,
three tyrosine containing SH2 domain binding sites
(Xu et al., 2007), of which a YXXM motif is for
PI3 kinase subunit p85 binding (Lodyga et al.,
2009). In the middle region, there are two pleckstrin
homology domains and another tyrosine binding
motif (Xu et al., 2007). The C-terminal contains a
coiled-coil region, which may be important for
molecular trafficking or dimerization (Xu et al.,
2007).
DNA/RNA
Note
Human XB130 was discovered in Dr. Mingyao
Liu's laboratory (University of Toronto) in the
process of cloning human actin filament associated
protein (afap) gene. Using chicken AFAP protein
sequence to search human cDNA library in
GenBank, XB130 was found as an EST clone
(GenBank accession number 1154093) with 34%
sequence similarity to chicken AFAP protein. The
clone contains partial coding sequence and 3' UTR.
The upstream sequence was obtained using 5' rapid
amplification of cDNA ends (RACE) from human
lung alveolar epithelial cell mRNA. Western blot
shows the protein molecular weight is 130 kD (Xu
et al., 2007).
In 2003, the XB130 knockout mice were
established through the collaboration of Drs.
Mingyao Liu and Tak W. Mak at the University of
Toronto.
Expression
In normal human tissue, the 4 kb mRNA transcript
of XB130 is expressed highly in spleen and thyroid
with lower expression in kidney, brain, lung and
pancreas (Xu et al., 2007).
Newer RNA sequencing by Illumina body map
using RNA obtained from 16 normal human tissues
shows high expression of XB130 in thyroid with
lower expression in lymph nodes, brain, colon,
adipocytes, kidney, lung, adrenal glands, breast,
ovary, prostate and testis followed by whole blood,
heart,
skeletal
muscles
and
liver
(www.genecards.org).
XB130 protein is detected in normal tissues of
thyroid, parathyroid, brain, kidney, skin and GItracks (www.proteinatlas.org).
XB130 protein expresses in human thyroid,
colorectal, gastric and hepatocellular carcinomas
(Shi et al., 2012; Shiozaki et al., 2013; Shiozaki et
al., 2011; Zuo et al., 2012). Expression of XB130
has also been observed in a variety of cancer cell
lines, including thyroid, lung, esophageal,
pancreatic and colon cancers (Shi et al., 2012;
Shiozaki et al., 2013; Zuo et al., 2012).
Description
Human xb130 genes contains 19 exons, which are
covering the whole coding sequence.
Transcription
The transcript size of xb130 is 3751 bp. There may
be 7 splicing variants based on Ensembl data
(www.ensembl.org). XB130 mRNA is highly
expressed in the thyroid, parathyroid and spleen;
moderately expressed in brain, pancreas, lung and
kidney.
Protein
Description
XB130 is a novel adaptor protein, member of the
actin filament associated protein (AFAP) family
(Snyder et al., 2011). Accordingly, it is also known
as AFAP1L2. The full length protein consists of
818 amino acids with a molecular weight of
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
629
AFAP1L2 (actin filament associated protein 1-like 2)
Bai X, et al.
lung, large intestine, ovary, skin, prostate,
endometrium.
Among these samples, 70% of identified cases are
XB130 substitution missense mutation.
Localisation
XB130 is distributed mainly in the cytoplasm and
perinuclear region of lung epithelial BEAS-2B cells
and several other cell types (Xu et al., 2007).
Unlike AFAP, XB130 does not associate or colocalize with actin filament stress fibler (Lodyga et
al., 2010).
Stimulation of cells with EGF, PMA, or
overexpression of constitutive Rac results in a
translocation of XB130 to the cell periphery and
leading edge of migrating cells (Lodyga et al.,
2010).
Implicated in
Various cancers
Note
XB130 plays important roles in tumor progression
by promoting cell proliferation, survival, motility
and invasion in various cancer cells.
Recently, XB130 has been identified in thyroid
carcinoma (Shiozaki et al., 2011), esophageal
squamous cell carcinoma (Shiozaki et al., 2013),
and gastric cancer (Shi et al., 2012).
Function
XB130 is an adaptor protein that acts as a key
mediator to drive signal transduction pathways.
XB130 has been shown to bind to tyrosine kinase cSrc to enhance kinase activity and subsequently
regulates Src-mediated AP-1/SRE transcription
activation (Xu et al., 2007).
XB130 is also highly involved in the PI3K/Akt
pathway and effects cell proliferation, cell cycle
progression and cell survival through binding to
p85 alpha subunit of PI3K (Lodyga et al., 2009).
XB130 may also play a role in the innate immune
response, where knockdown of XB130 was shown
to decrease IL-6 and IL-8 cytokine levels in human
lung epithelial cells (Xu et al., 2007). XB130 is also
involved in cell migration via association with RacGTPase and plays a significant role in lateral cell
migration and cell invasion in both normal and
cancer cell lines (Lodyga et al., 2010).
Yamanaka et al. reported phosphorylated XB130
affects cAMP-dependent DNA synthesis in rat
thyroid cells (Yamanaka et al., 2012). XB130 is
aberrantly expressed in human cancers and has been
shown to control tumour growth in vivo (Shiozaki
et al., 2011).
XB130 regulates thyroid cancer cell proliferation
by controlling microRNA miR-33a, 149a and 193a
expression to alter oncogenes Myc, FosL1, and
SCL7A5 protein levels (Takeshita et al., 2013).
Colorectal cancer
Note
Tyrosine phosphorylated XB130 in colorectal
cancer.
Prognosis
Using mass spectrometry, Emaduddin et al.
reported several proteins as tyrosine phosphorylated
form are maintained at high level in colorectal
cancer cells isolated from patients.
XB130 is identified as one of these proteins.
Therefore, tyrosine phosphorylated XB130 has a
potential to be a biomarker of colorectal cancer
(Emaduddin et al., 2008).
Gastric cancer (GC)
Note
XB130 expression level associates with the
prognosis of gastric cancer.
Prognosis
Based on the anlysis GC tissue samples from 411
patients with various stages, lower expression of
XB130 mRNA as well as protein is significantly
correlated with reduced patient survival time and
shorter disease-free period (Shi et al., 2012).
Homology
Thyroid cancer
XB130 shares similar sequence and domain
structure cellular as AFAP and AFAP1L1 (Snyder
et al., 2011).
Note
XB130 as a tumor promoting gene, enhancing
thyroid cancer cell growth.
Oncogenesis
Knockdown XB130 using siRNA in thyroid cancer
cell (WRO) is accompanied with an inhibition of
G1-S phase cell cycle progression and enhanced
apoptosis.
The volume of tumors generated in nude mice after
injecting these cells are smaller than those formed
from cells with a normal XB130 expression
(Shiozaki et al., 2011).
Mutations
Somatic
Somatic mutations of XB130 are reported in a
variety of cancer tissues.
Based on the data of Sanger Institute database
(www.sanger.ac.uk), XB130 mutation sites have
been identified in multiple tumor tissues, including
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
630
AFAP1L2 (actin filament associated protein 1-like 2)
Bai X, et al.
Esophageal squamous cell
carcinoma (ESCC)
is a Rac-controlled component of lamellipodia that
regulates cell motility and invasion. J Cell Sci. 2010 Dec
1;123(Pt 23):4156-69
Note
XB130 protein is identified in ESCC primary cell
lines and tumor samples.
Oncogenesis
XB130 protein is highly expression in ESCC
primary cells. XB130 protein is examined by
immunohistochemistry staining from ESCC tissues
collected from 52 patients. Positive XB130 staining
is observed in 71% of ESCC samples, which
indicates the association of XB130 protein and
ESCC (Shiozaki et al., 2013).
Shiozaki A, Liu M. Roles of XB130, a novel adaptor
protein, in cancer. J Clin Bioinforma. 2011 Mar 17;1(1):10
Shiozaki A, Lodyga M, Bai XH, Nadesalingam J, Oyaizu T,
Winer D, Asa SL, Keshavjee S, Liu M. XB130, a novel
adaptor protein, promotes thyroid tumor growth. Am J
Pathol. 2011 Jan;178(1):391-401
Snyder BN, Cho Y, Qian Y, Coad JE, Flynn DC, Cunnick
JM. AFAP1L1 is a novel adaptor protein of the AFAP
family that interacts with cortactin and localizes to
invadosomes. Eur J Cell Biol. 2011 May;90(5):376-89
Shi M, Huang W, Lin L, Zheng D, Zuo Q, Wang L, Wang
N, Wu Y, Liao Y, Liao W. Silencing of XB130 is associated
with both the prognosis and chemosensitivity of gastric
cancer. PLoS One. 2012;7(8):e41660
Soft tissue tumor
Note
Decreased XB130 expression leads to a local
aggressiveness of soft tissue tumor.
Oncogenesis
Analysis of gene expression profile of 102 tumor
samples with varying stages of soft tissue tumor
shows a decreased XB130 expression in malignant
mesenchymal tumors (Cunha et al., 2010).
Shiozaki A, Shen-Tu G, Bai X, Iitaka D, De Falco V,
Santoro M, Keshavjee S, Liu M. XB130 mediates cancer
cell proliferation and survival through multiple signaling
events downstream of Akt. PLoS One. 2012;7(8):e43646
References
Zuo Q, Huang H, Shi M, Zhang F, Sun J, Bin J, Liao Y,
Liao W. Multivariate analysis of several molecular markers
and clinicopathological features in postoperative prognosis
of hepatocellular carcinoma. Anat Rec (Hoboken). 2012
Mar;295(3):423-31
Yamanaka D, Akama T, Fukushima T, Nedachi T,
Kawasaki C, Chida K, Minami S, Suzuki K, Hakuno F,
Takahashi S. Phosphatidylinositol 3-kinase-binding
protein, PI3KAP/XB130, is required for cAMP-induced
amplification of IGF mitogenic activity in FRTL-5 thyroid
cells. Mol Endocrinol. 2012 Jun;26(6):1043-55
Xu J, Bai XH, Lodyga M, Han B, Xiao H, Keshavjee S, Hu
J, Zhang H, Yang BB, Liu M. XB130, a novel adaptor
protein for signal transduction. J Biol Chem. 2007 Jun
1;282(22):16401-12
Shiozaki A, Kosuga T, Ichikawa D, Komatsu S, Fujiwara H,
Okamoto K, Iitaka D, Nakashima S, Shimizu H, Ishimoto T,
Kitagawa M, Nakou Y, Kishimoto M, Liu M, Otsuji E.
XB130 as an independent prognostic factor in human
esophageal squamous cell carcinoma. Ann Surg Oncol.
2013 Sep;20(9):3140-50
Emaduddin M, Edelmann MJ, Kessler BM, Feller SM. Odin
(ANKS1A) is a Src family kinase target in colorectal cancer
cells. Cell Commun Signal. 2008 Oct 9;6:7
Lodyga M, De Falco V, Bai XH, Kapus A, Melillo RM,
Santoro M, Liu M. XB130, a tissue-specific adaptor protein
that couples the RET/PTC oncogenic kinase to PI 3-kinase
pathway. Oncogene. 2009 Feb 19;28(7):937-49
Takeshita H, Shiozaki A, Bai XH, Iitaka D, Kim H, Yang
BB, Keshavjee S, Liu M. XB130, a new adaptor protein,
regulates expression of tumor suppressive microRNAs in
cancer cells. PLoS One. 2013;8(3):e59057
Cunha IW, Carvalho KC, Martins WK, Marques SM, Muto
NH, Falzoni R, Rocha RM, Aguiar S, Simoes AC, Fahham
L, Neves EJ, Soares FA, Reis LF. Identification of genes
associated with local aggressiveness and metastatic
behavior in soft tissue tumors. Transl Oncol. 2010
Feb;3(1):23-32
This article should be referenced as such:
Bai X, Moodley S, Cho HR, Liu M. AFAP1L2 (actin filament
associated protein 1-like 2). Atlas Genet Cytogenet Oncol
Haematol. 2014; 18(9):628-631.
Lodyga M, Bai XH, Kapus A, Liu M. Adaptor protein XB130
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
631
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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OPEN ACCESS JOURNAL
Gene Section
Review
ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Xiaoyu Tang, Dorothy M Morré, D James Morré
MorNuCo, Inc., 1201 Cumberland Avenue, Ste. B, Purdue Research Park,.West Lafayette, IN 47906
USA (XT, DMM, DJM)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/ENOX2ID40134chXq26.html
DOI: 10.4267/2042/54027
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
according to NCBI Refseq Gene Database (gene
ID: 10495, RefSeq ID: NG_012562.1), and is
comprised of 279939 bp.
ENOX2 is composed of 13 protein-coding exons
between 71 bp and 2066 bp in length and 14 introns
which vary greatly in length (1781 bp to 117994
bp).
It has a 501 bp 5' untranslated region and a long 3'
UTR (approximately 1935 bp).
Abstract
Review on ENOX2, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Identity
Other names: APK1, COVA1, tNOX
HGNC (Hugo): ENOX2
Location: Xq26.1
Note
Also termed APK1 antigen, or cytosolic ovarian
carcinoma antigen 1, or tumor-associated
hydroquinone oxidase (tNOX).
ECTO-NOX2 = Ecto-Nicotinamide Dinucleotide
Oxidase Disulfide Thiol Exchange 2.
Transcription
According to NCBI the human ENOX2 gene
encodes a 4036 bp mRNA transcript, the coding
sequence (CDS) located from base pairs 356 to
2101 (NM_001281736.1).
The CDS from the Ensembl genome browser
database (ENST00000370927, transcript length
3788 bp) and NCBI (NM_001281736.1) are
identical.
Transcripts
NM_001281736.1
and
ENST
00000370927 are also included in the human CCDS
set (CCDS14626) and encode a 610 aa long protein.
DNA/RNA
Description
Pseudogene
The human ENOX2 gene is located on the reverse
strand of chromosome X (bases 4918 to 284856);
None known.
Figure 1. ENOX2 mRNA.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
632
ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Tang X, et al.
Figure 2. Deduced amino acid sequence and functional motifs of the bacterially expressed 46 kDa enzymatically active Cterminus of ENOX2.
for protein disulfide-thiol interchange (Morré and
Morré, 2013).
The signature ENOX2 motif is that of the potential
drug/antibody binding site E394EMTE. Antisera
directed to this portion of the protein act as
competitive inhibitors to drug binding. The
sequence provides a putative quinone or
sulfonylurea-binding site with four of the five
amino acids in at least one other putative quinone
site in the same relative positions.
The correctness of the various assignments has, for
the most part, been confirmed by site-directed
mutagenesis (Chueh et al., 2002).
While amino acid replacements that block oxidation
of reduced pyridine nucleotide by ENOX2 also
eliminated protein disulfide-thiol interchange and
vice versa (Chueh et al., 2002), the two activities
appear to occur independently.
One can be measured in the absence of the other.
The ENOX2 proteins have properties of prions and
are protease resistant (Kelker et al., 2001) and Nterminal sequencing.
Concentrated solutions aggregate and form
amyloid-like filaments.
Protein
Description
ENOX2 transcription variants all appear to be
variations that include an exon 4 minus splicing
event that allows for down-stream initiation and
expression of the ENOX2 protein at the cell surface
of malignant cells (Tang et al., 2007a; Tang et al.,
2007b). Without the exon 4 deletion, mRNA
derived from the gene does not appear to be
translated into protein. Thus, the exon 4 deletion is
the basis for the cancer specificity of the ENOX2
transcription variants. An hnRNP splicing factor
directs formation of the Exon 4 minus variants of
ENOX2 (Tang et al., 2011). The fully processed 34
kDa generic ENOX2 protein found on the cell
surface of HeLa cells and in sera of about 23% of
early cancer patients retains full-functional activity.
The deduced amino acid sequence of a bacterially
expressed 46 kDa functional C-terminus of ENOX2
exhibits the same characteristics of alternation of
the two activities and drug response as the cell
surface and generic serums forms. Identified
functional motifs include a quinone binding site, an
adenine nucleotide binding site, a CXXXXC
cysteine motif as a potential disulfide-thiol
interchange site and two copper binding sites, one
of which is conserved with superoxide dismutase.
ENOX2 proteins lack flavin and only one of the
two C-X-X-X-X-C motifs characteristic of
flavoproteins are present in ENOX2. Yet the
protein effectively carries out protein disulfide
interchange. The motif C569-X-X-X-X-X-C575,
alone or together with a downstream histidine
(H582) provides an additional potential active site
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Expression
Widely expressed in malignant cells but only as
exon 4 minus splicing variants (Tang et al., 2007b).
Localisation
External cell surface (Morré, 1995).
Function
ENOX2 is a member of a family of cell surface
metalocatalysts with binuclear copper centers that
oscillate.
633
ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Tang X, et al.
Figure 3. Diagrammatic representation of the functional unit of the ENOX2 proteins which is a dimer, each monomer of which
contains two copper centers. During the oxidative portion of the ENOX cycle on the right, the net result is the transfer of 4
electrons plus 4 protons to molecular oxygen to from 2H2O. The left portion of the diagram illustrates the protein disulfide-thiol
interchange activity portion of the cycle where the result is an interchange of protons and electrons that results in the breakage
and formation of disulfide bonds important to cell enlargement.
They catalyze both NAD(P)H and hydroquinone
oxidation in one configuration and carry out protein
disulfide-thiol
interchange
in
a
second
configuration (Figure 3). The two activities
alternate creating a regular 22 min period to impart
a time-keeping function (Morré and Morré, 2003).
The oscillations are highly synchronous and phased
by low frequency electromagnetic fields.
Functionally ENOX2 proteins of cancer cells act as
terminal oxidases of plasma membrane electron
transport (PMET) whereby electrons coming from
cytosolic NAD(P)H are transferred to membranelocated coenzyme Q with eventual transfer of
electrons and proteins to oxygen to form water
(Figure 4). The released energy is presumably
utilized to drive cell enlargement. The protein
disulfide-thiol interchange part of the cycle carries
out a function essential to the cell enlargement
mechanism (Morré et al., 2006). The phenotype of
unregulated accelerated growth is recapitulated in a
transgenic mouse strain over expressing human
ENOX2 (Yagiz et al., 2006).
The ENOX2 gene is present in the human genome
as a single copy, with no obvious homologs and a
single constitutive ENOX1 (CNOX) ortholog with
64% identity and 80% similarity (Jiang et al.,
2008).
Mutations
Somatic
No reports of mutations leading to inactivation of or
inability to express ENOX2.
Implicated in
Various cancers
Note
The ENOX2 protein is universally associated with
malignancies. It is not the result of an oncogenic
mutation but appears to be similar if not identical to
a form of ENOX protein with characteristics of an
oncofetal protein important to maintenance of
unregulated growth in very early development that
may be re-expressed in malignancy (Cho and
Morré, 2009). Re-expression as an oncofetal protein
helps explain the role of ENOX2 of cancer cells in
acquiring the well-known characteristic of
uncontrolled growth. Consistent with this
interpretation are observations that the malignant
phenotypes of invasiveness and growth on soft agar
of cancer cells in culture are lost when cells are
transfected with ENOX2 antisense (Chueh et al.,
2004; Tang et al., 2007a).
Homology
RNA recognition motif (RRM) in the cell surface
Ecto-NOX disulfide-thiol exchanger (ECTO-NOX
or ENOX) proteins. This subgroup corresponds to
the conserved RNA recognition motif (RRM) in
ECTO-NOX proteins (also termed ENOX),
comprising a family of plant and animal NAD(P)H
oxidases exhibiting both oxidative and protein
disulfide-like activities.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Tang X, et al.
Figure 4. Schematic representation of the utility of the ENOX2 proteins as cancer-specific cell surface proteins for diagnosis and
therapeutic intervention in cancer. Modified from Morré and Morré (2013).
ENOX2 is the first reported cell surface change
absent from non-cancer cells and associated with
most, if not all, forms of human cancer (Morré and
Morré, 2013).
As such, ENOX2 emerges as a potential universal
molecular cancer marker and, being an ecto-protein
at the cell surface and shed into the circulation, a
reliable cancer diagnostic marker both for cancer
presence and tissue of cancer origin (Figure 4).
ENOX2 proteins are expressed differently by
different tissues of cancer origin within the body
with each type of cancer being characterized by
one, two, three or more tissue specific transcript
variants of characteristic molecular weights and
isoelectric points (Morré and Morré, 2012).
ENOX2 proteins are absent or reduced to below the
limits of detection from sera of healthy individuals
or patients with diseases other than cancer.
Circulating ENOX2 has been detected in sera of
patients representing all major forms of human
cancer including leukemias and lymphomas.
All ENOX2 transcript variants appear to share the
common antigenic determinant recognized both by
an ENOX2-specific monoclonal antibody (Cho et
al., 2002) and a corresponding scFv single chain
variable region recombinant antibody expressed in
bacteria and derived from the monoclonal antibodyproducing hybridoma cells with analysis by 2-D-gel
electrophoresis and western blot (Hostetler et al.,
2009).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Breast cancer
Note
Sera of breast cancer patients contains an ENOX2
transcript variant of 64 to 69 kDa, isoelectric point
4.2 to 4.9.
Lung cancer
Note
Sera of patients with non-small cell lung cancer
contain a 53 to 56 kDa ENOX2 transcript variant,
isoelectric point pH 4.7 to 5.3 while sera of small
cell lung cancer contain a transcript variant of 52
kDa, isoelectric point pH 4.1 to 4.6.
Prostate cancer
Note
Sera of patients with prostate cancer contain a 71 to
88 kDa ENOX2 transcript variant, isoelectric point
pH 5.1 to 6.5.
Cervical cancer
Note
Sera of cervical cancer patients contain a 90 to 100
kDa transcript variant, isoelectric point pH 4.2 to
5.4.
Malignant melanoma
Note
Sera from malignant melanoma patients contain an
ENOX2 transcript variant of 37 to 41 kDa,
635
ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Tang X, et al.
isoelectric point pH 4.6 to 5.3.
by anticancer drugs such as doxorubicin, the
anticancer sulfonylureas, the vanilloid capsaicin,
the catechin EGCg and the cancer isoflavene
phenoxodiol, all of which appear to function as
quinone site inhibitors directed toward the EEMTE
drug binding motif of ENOX2 (Morré and Morré,
2013; Hanau et al., 2014). The possibility of
ENOX2 as a drug target is enhanced by the external
location of the ENOX2 protein in a position to be
readily available to drugs or antibodies conjugated
to impermeant supports. As the growth involvement
of ENOX2 proteins is in cell enlargement, ENOX2
inhibitors also block cell proliferation. The blocked
cells, unable to enlarge, also fail to divide and
eventually undergo apoptosis (Figure 4).
Leukemias, lymphomas and
myelomas
Note
Sera of patients with leukemia, lymphoma or
myeloma, cancers having blood as the common
tissue of origin, all contain ENOX2 transcript
variants of 38 to 48 kDa and low isoelectric point
pH 3.6 to 4.5.
Ovarian cancer
Note
Sera from ovarian carcinoma patients contain two
ENOX2 transcript variants of 72 to 90 kDa and 37
to 47 kDa, both having similar isoelectric points in
the range of pH 3.7 to 5.0.
References
Bladder cancer
Morré DJ. NADH oxidase activity of HeLa plasma
membranes inhibited by the antitumor sulfonylurea N-(4methylphenylsulfonyl)-N'-(4-chlorophenyl)
urea
(LY181984) at an external site. Biochim Biophys Acta.
1995 Dec 13;1240(2):201-8
Note
Sera of patients with carcinoma of the bladder
contain two ENOX2 transcript variants of 63 to 66
kDa and 42 to 48 kDa with isoelectric points of 4.2
to 5.8 and 4.1 to 4.8, respectively.
Kelker M, Kim C, Chueh PJ, Guimont R, Morré DM, Morré
DJ. Cancer isoform of a tumor-associated cell surface
NADH oxidase (tNOX) has properties of a prion.
Biochemistry. 2001 Jun 26;40(25):7351-4
Uterine cancer
Note
Sera of patients with uterine carcinoma contain two
ENOX2 transcript variants of 64 to 69 kDa and 36
to 48 kDa with isoelectric points of pH 4.2 to 4.9
and pH 4.5 to 5.6.
Cho N, Chueh PJ, Kim C, Caldwell S, Morré DM, Morré
DJ. Monoclonal antibody to a cancer-specific and drugresponsive hydroquinone (NADH) oxidase from the sera of
cancer patients. Cancer Immunol Immunother. 2002
May;51(3):121-9
Chueh PJ, Kim C, Cho N, Morré DM, Morré DJ. Molecular
cloning and characterization of a tumor-associated,
growth-related, and time-keeping hydroquinone (NADH)
oxidase (tNOX) of the HeLa cell surface. Biochemistry.
2002 Mar 19;41(11):3732-41
Colorectal cancer
Note
Sera of patients with colorectal cancer contain at
least two of three possible ENOX2 transcript
variants of 80 to 96 kDa, isoelectric point pH 4.5 to
5.3, 50 to 60 kDa, isoelectric point pH 4.2 to 5.1
and 33 to 46 kDa, isoelectric point pH 3.8 to 5.2.
Morré DJ, Morré DM. Cell surface NADH oxidases (ECTONOX proteins) with roles in cancer, cellular time-keeping,
growth, aging and neurodegenerative diseases. Free
Radic Res. 2003 Aug;37(8):795-808
Other cancers
Chueh PJ, Wu LY, Morré DM, Morré DJ. tNOX is both
necessary and sufficient as a cellular target for the
anticancer actions of capsaicin and the green tea catechin
(-)-epigallocatechin-3-gallate. Biofactors. 2004;20(4):23549
Note
Unique patterns of ENOX2 transcript variant
expression (number, molecular with and isoelectric
point) have been found as well associated with
brain,
endometrial,
esophageal,
gastric,
hepatocellular renal cell, squamous cell, testicular
germ cell and thyroid cancer as well as
mesothelioma and sarcomas.
Morré DJ, Kim C, Hicks-Berger C. ATP-dependent and
drug-inhibited vesicle enlargement reconstituted using
synthetic lipids and recombinant proteins. Biofactors.
2006;28(2):105-17
Yagiz K, Morré DJ, Morré DM. Transgenic mouse line
overexpressing the cancer-specific tNOX protein has an
enhanced growth and acquired drug-response phenotype.
J Nutr Biochem. 2006 Nov;17(11):750-9
Endometriosis
Note
Invasive endometriosis is the only non-malignant
disorder thus far characterized by the presence of
unique ENOX2 transcript variants.
Tang X, Morré DJ, Morré DM. Antisense experiments
demonstrate an exon 4 minus splice variant mRNA as the
basis for expression of tNOX, a cancer-specific cell surface
protein. Oncol Res. 2007a;16(12):557-67
As a cancer therapeutic drug target
Tang X, Tian Z, Chueh PJ, Chen S, Morré DM, Morré DJ.
Alternative splicing as the basis for specific localization of
tNOX, a unique hydroquinone (NADH) oxidase, to the
cancer
cell
surface.
Biochemistry.
2007b
Oct
30;46(43):12337-46
Note
ENOX2 is responsive to differentiating agents such
as calcitriol and anticancer retinoids and inhibited
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
636
ENOX2 (ecto-NOX disulfide-thiol exchanger 2)
Tang X, et al.
Jiang Z, Gorenstein NM, Morré DM, Morré DJ. Molecular
cloning and characterization of a candidate human growthrelated and time-keeping constitutive cell surface
hydroquinone (NADH) oxidase. Biochemistry. 2008 Dec
30;47(52):14028-38
Morre DJ, Morre DM.. Early detection: an opportunity for
cancer prevention through early intervention. In:
Georgakilas
AG
(ed),
Cancer
Prevention.
http://www.intechopen.com/download/pdf/35600. In Tech,
Rijeka, 2012:389-402 pp.
Cho N, Morré DJ. Early developmental expression of a
normally tumor-associated and drug-inhibited cell surfacelocated NADH oxidase (ENOX2) in non-cancer cells.
Cancer Immunol Immunother. 2009 Apr;58(4):547-52
Morre DJ, Morre DM.. ECTO-NOX Proteins. ISBM 978-14614-3957-8. Springer, New York, 2013, 507 pp.
Hanau C, Morre DJ, Morre DM.. Cancer prevention trial of
a synergistic mixture of green tea concentrate plus
Capsicum (CAPSOL-T) in a random population of subjects
ages
40-84.
http://link.springer.com/content/pdf/10.1007%252Fs12014008-9016-x. Clin Proteomics 2014: 11(2).
Hostetler B, Weston N, Kim C, Morre DM, Morre DJ..
Cancer site-specific isoforms of ENOX2 (tNOX), a cancerspecific
cell
surface
oxidase.
http://link.springer.com/content/pdf/10.1007%252Fs12014008-9016-x. Clin Proteomics 2009:5:46-51.
This article should be referenced as such:
Tang X, Kane VD, Morre DM, Morre DJ.. hnRNP F directs
formation of an exon 4 minus variant of tumor-associated
NADH oxidase (ENOX2). Mol Cell Biochem. 2011
Nov;357(1-2):55-63. doi: 10.1007/s11010-011-0875-5.
Epub 2011 May 28.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Tang X, Morré DM, Morré DJ. ENOX2 (ecto-NOX disulfidethiol exchanger 2). Atlas Genet Cytogenet Oncol
Haematol. 2014; 18(9):632-637.
637
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
FABP7 (fatty acid binding protein 7, brain)
Roseline Godbout, Ho-Yin Poon, Rong-Zong Liu
Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue,
Edmonton, Alberta, T6G 1Z2 Canada (RG, HYP, RZL)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/FABP7ID46256ch6p22.html
DOI: 10.4267/2042/54028
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Local order: PKIB → FABP7 → SMPDL3A.
Abstract
DNA/RNA
Review on FABP7, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
Description
The FABP7 gene is 4,5 kb long and contains 4
exons, all of which contain coding sequences.
The following FABP7 SNPs have been validated: 7
in the 3' UTR, 6 in the 5' UTR, 5 missense and 4
SNPs in the coding region that don't alter the amino
acid code (dbSNP).
Identity
Other names: B-FABP, BLBP, FABPB, MRG
HGNC (Hugo): FABP7
Location: 6q22.31
FABP7 gene. The FABP7 gene is located on chromosome 6 in the region of q22-q23 on the positive strand. Neighboring genes
are indicated.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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FABP7 (fatty acid binding protein 7, brain)
Godbout R, et al.
Crystal structure of FABP7 bound to DHA. The structure of FABP7 is similar to that of other FABPs and consists of two Nterminal α-helices attached to a β-barrel motif (left). Three amino acids are predicted to be important for fatty acid binding: F104
(fuchsia), arginine 126 (red) and Y128 (teal) based on the structure of FABP7 bound to DHA. DHA is shown in yellow (right).
Structural data were obtained from the Protein Data Bank (PDB ID: 1FE3) (Balendiran et al., 2000) and rendered using PyMOL
(Beaulieu, 2012).
Based on EST data, FABP7 RNA is most highly
expressed in the fetus, followed by adult brain, eye,
connective tissue, bone, heart, kidney, mammary
gland, skin, uterus, lung and testis.
Transcription regulators: Members of the nuclear
factor I (NFI) family regulate the transcription of
the FABP7 gene (Bisgrove et al., 2000; Brun et al.,
2009).
The phosphorylation state of NFI determines its
regulatory activity, with FABP7 transcription upregulated by hypophosphorylated NFI (Bisgrove et
al., 2000; Brun et al., 2013). Other transcription
factors implicated in the regulation of FABP7
include Notch (Anthony et al., 2005), PAX6 (Arai
et al., 2005; Numayama-Tsuruta et al., 2010; Liu et
al., 2012b), and POU-domain protein PBX-1
(Josephson et al., 1998).
Furthermore, ligands of peroxisome proliferatoractivated receptors (PPARs) such as clofibrate and
omega-3 docosahexaenoic acid (DHA) have been
shown to up-regulate FABP7 expression
(Nasrollahzadeh et al., 2008; Venkatachalam et al.,
2012).
Post-transcriptional regulation: The 3' untranslated
region of FABP7 contains phylogenetically
conserved cytoplasmic polyadenylation elements
(CPE) which have been implicated in the trafficking
and localized translation of FABP7 at perisynaptic
processes of astrocytic cells (Gerstner et al., 2012).
Protein
Description
FABP7 is a member of the intracellular lipidbinding protein family. FABP7 is a 132 amino acid
polypeptide with an estimated molecular mass of 15
kDa.
It has a beta-clam structure made up of ten antiparallel beta sheets capped by two alpha helices.
Fatty acid ligands reside inside the beta-clam
structure.
Expression
FABP7 is expressed in radial glial cells during
brain development (Feng et al., 1994). FABP7
persists in specific regions of the mature mouse
brain, including glia limitans, in radial glial cells of
the hippocampal dentate gyrus and Bergman glial
cells (Kurtz et al., 1994). FABP7 is also expressed
in glial cells of the peripheral nervous system, and
ensheathing cells of the olfactory nerve (Kurtz et
al., 1994).
Localisation
The FABP7 protein is found in both the cytoplasm
and nucleus of normal radial glial cells (Feng et al.,
1994) and tumor cells (Liang et al., 2006; Slipicevic
et al., 2008). FABP7 is also found in perisynaptic
processes of astrocytes with localized translation of
FABP7 at these sites (Gerstner et al., 2012).
Pseudogene
Function
A predicted FABP7 pseudogene is located on
chromosome 1 (NCBI nucleotide database
NG_029025.1). There are two inferred human
FABP7 pseudogenes listed in the Rat Genome
Database
(http://rgd.mcw.edu/rgdweb/report/gene/main.html?
id=5132511
on
chromosome
1
and
http://www.rgd.mcw.edu/rgdweb/report/gene/main.
html?id=6481032 on chromosome 2).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Recombinant human FABP7 exhibits the highest
affinity for the polyunsaturated omega-3 fatty acids
α-linolenic
acid,
eicosapentaenoic
acid,
docosahexaenoic acid, and for monounsaturated
omega-9 oleic acid (Kd from 28 to 53 nM) and
moderate affinity for the polyunsaturated omega-6
fatty acids, linoleic acid and arachidonic acid (AA)
(Kd from 115 to 206 nM) (Balendiran et al., 2000).
639
FABP7 (fatty acid binding protein 7, brain)
Godbout R, et al.
FABP7 has low binding affinity for saturated long
chain fatty acids. Human FABP7 enhances DHA
trafficking to the nucleus (Mita et al., 2010).
FABP7 is required for the establishment of the
radial glial fiber system along which neurons
migrate in order to reach their correct destination in
the developing brain (Feng et al., 1994). FABP7 is
also required for the maintenance of neuroepithelial
cells in rat cortex (Arai et al., 2005). FABP7 knockout mice have a structurally normal brain; however,
the mice show enhanced anxiety and increased fear
memory, as well as decreased DHA in neonatal
brain and increased AA in adult brain amygdala
(Owada et al., 2006).
increased cell migration (Liang et al., 2005). A role
for FABP7 in malignant glioma cell migration was
confirmed by Mita et al. (2007) who used human
U87 malignant glioma cell lines stably transfected
with a FABP7 expression construct to demonstrate
a correlation between FABP7 expression and
increased cell migration.
In agreement with a role for FABP7 in migration
and infiltration, FABP7 was found to be
preferentially expressed at sites of infiltration and
surrounding blood vessels in glioblastoma
multiforme (Mita et al., 2007).
Growth of malignant glioma cell lines in the
presence of polyunsaturated fatty acids omega-3
DHA and omega-6 AA indicates that the ratio of
AA:DHA affects migration in FABP7-positive
cells, with a higher DHA:AA ratio resulting in
decreased migration (Mita et al., 2010). These
results suggest that glioblastoma tumour growth
and infiltration may be controlled by increasing
levels of DHA in tumour tissue (Elsherbiny et al.,
2013).
Neurospheres
derived
from
glioblastoma
multiforme express high levels of FABP7,
suggesting the presence of FABP7-positive neural
stem-like cells in glioblastoma (De Rosa et al.,
2012).
In keeping with this possibility, FABP7 is
preferentially expressed in the subset of
glioblastoma tumour cells that express the neural
stem cell marker CD133 (Liu et al., 2009). Knockdown of FABP7 in glioblastoma-derived
neurosphere cultures results in decreased cell
migration and reduced proliferation (De Rosa et al.,
2012).
The FABP7 promoter has been shown to be
hypomethylated in glioblastoma tumours compared
to normal brain (Etcheverry et al., 2010).
Homology
Human FABP7 amino acid sequence is 86,4%
identical to mouse FABP7, 90,9% identical to
chicken FABP7, 82,6% identical to zebrafish
FABP7a and 78% identical to zebrafish FABP7b.
Human FABP7 shows variable sequence identity
with the other FABP paralogues, with the lowest
identity to FABP1 (27,6%) and highest identity to
FABP3 (65,9%).
Mutations
Note
With the exception of SNPs, no mutations in the
FABP7 gene have been reported.
Implicated in
Malignant glioma (grades III and IV
astrocytoma) / glioblastoma
multiforme (grade IV astrocytoma)
Note
FABP7 was first reported to be expressed in
malignant glioma cell lines and malignant glioma
tumour tissue in 1998 (Godbout et al., 1998). Liang
et al. (2005) used gene expression profiling to
demonstrate that FABP7 RNA levels were elevated
in glioblastoma tumours compared to normal brain.
These authors showed that elevated levels of
nuclear FABP7 protein were associated with
decreased survival in patients with glioblastoma
multiforme, particularly in younger patients.
Subsequent analysis of 123 glioblastomas by
Kaloshi et al. (2007) revealed a correlation between
nuclear FABP7, EGFR amplification and more
invasive tumours. De Rosa et al. (2012) also
showed a correlation between elevated FABP7
levels and decreased survival in patients with
glioblastoma multiforme.
Transfection of a FABP7 expression construct into
the SF767 malignant glioma cell line results in
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Breast cancer
Note
MRG (mammary-derived growth inhibitor-related
gene), later shown to be identical to FABP7
(Hohoff and Spener, 1998), was reported to be
expressed in normal and benign breast tissue but
only rarely in breast cancer (1 of 10 infiltrative
breast cancers and 2 of 12 ductal carcinomas in
situ) (Shi et al., 1997). Transfection of a MRG
expression construct into the MDA-MB-231 breast
cancer cell line suppressed cell proliferation and
tumour growth in an orthotopic mouse model (Shi
et al., 1997). Subsequent work showed that MRG
over-expression induced differentiation in human
breast cancer cells and that treatment of breast
cancer cells with DHA causes MRG-dependent
growth inhibition (Wang et al., 2000).
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FABP7 (fatty acid binding protein 7, brain)
Godbout R, et al.
FABP7 mRNA levels are upregulated in human glioblastoma. Comparison of FABP7 mRNA levels in normal human brain
versus glioblastoma tissues. Database obtained from Oncomine website (www.oncomine.org; Bredel Brain 2).
ligands available to nuclear receptors such as
PPARs, understanding the roles of cytoplasmic and
nuclear FABP7 will help elucidate its biological
functions in breast cancer.
Preferential expression of FABP7 in estrogen
receptor-negative breast cancer compared to
estrogen receptor-positive breast cancer has been
reported by four separate groups (Tang et al., 2010;
Zhang et al., 2010; Graham et al., 2011; Liu et al.,
2012a). In an analysis of 176 primary breast
cancers, Liu et al. (2012) found a correlation
between elevated FABP7 levels and poor
prognosis. These authors further showed that
depletion of FABP7 in FABP7-positive/estrogennegative MDA-MB-435S, reduced cell growth and
sensitized the cells to growth inhibition by DHA. In
addition, FABP7 was found to mediate DHAinduced retinoid-X-receptor beta (RXRβ) activation
in triple-negative BT-20 breast cancer cells as well
as MDA-MB-435S cells. In a study of 899 invasive
breast cancer cases, Zhang et al. (2010) showed that
basal breast cancers (estrogen/progesterone
receptor-negative, HER2-negative) that were
FABP7-positive had significantly better outcomes
than basal breast cancers that were FABP7negative. Analysis of the subcellular localization of
FABP7 in 1249 unselected and 245 estrogen
receptor-negative invasive breast cancers revealed
both nuclear and cytoplasmic staining patterns, with
nuclear FABP7 associated with a high histological
grade, stage, mitotic frequency, as well as basal and
triple-negative status (Alshareeda et al., 2012).
Within the basal category, elevated levels of
nuclear FABP7 were associated with longer
disease-free survival. In light of the proposed roles
for nuclear FABPs in making their fatty acid
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Renal cell carcinoma
Note
FABP7 RNA and protein are up-regulated in renal
cell carcinoma compared to normal kidney tissue
(Seliger et al., 2005; Teratani et al., 2007; Domoto
et al., 2007). Analysis of a tissue microarray
containing 272 renal cell carcinomas showed
significantly lower levels of FABP7 in grades 3 and
4 compared to grades 1 and 2 renal cell carcinomas
(Tölle et al., 2009). No correlation was found
between patient survival and FABP7 staining
intensity. In agreement with malignant glioma
experiments, knock-down of FABP7 in human
kidney carcinoma cells resulted in decreased cell
migration (Tölle et al., 2011).
The regulation of FABP7 in renal cell carcinoma
has been addressed by analysing the FABP7
promoter (Takaoka et al., 2011). This analysis
indicates that BRN2 (POU3F2) and nuclear factor I
(NFI) may be regulating the expression of FABP7
in renal cell carcinoma.
Melanoma
Note
FABP7 been reported to be both down-regulated in
melanoma compared to benign nevi (de Wit et al.,
2005) and widely expressed in melanoma (Goto et
641
FABP7 (fatty acid binding protein 7, brain)
Godbout R, et al.
with schizophrenia were up-regulated in the
dorsolateral prefrontal cortex. Furthermore, single
nucleotide polymorphism (SNP) analysis revealed
an association between missense polymorphism
Thr61Met 182C>T) and male patients with
schizophrenia (Watanabe et al., 2007).
In a separate study, FABP7 SNPs F704, F705 and
F709 showed nominal association with bipolar
disorder (Iwayama et al., 2010). Analysis of 6
FABP7 variants identified by polymorphic screen
failed to identify any associations with autism or
schizophrenia in 285 autistic and 1060
schizophrenic patients of Japanese descent
(Maekawa et al., 2010).
al., 2010). FABP7 immunostaining of 149 primary
melanomas revealed an association between
FABP7 expression and tumour thickness, as well as
a trend towards increased relapse-free survival for
patients who had tumors with low cytoplasmic
FABP7 levels (Slipicevic et al., 2008). Knockdown of FABP7 in human melanoma cells resulted
in decreased cell proliferation and invasion. There
was no association between the nuclear expression
of FABP7 and patient survival in this study
(Slipicevic et al., 2008).
Gene expression analysis of 87 primary melanomas
and 68 metastatic melanoma, combined with
immunohistochemical analysis of 37 paired primary
and metastatic melanomas, showed significantly
decreased FABP7 levels in metastatic melanoma
compared to primary tumor tissue (Goto et al.,
2010). In metastatic melanoma, FABP7 mRNA
expression was associated with decreased relapsefree survival and overall survival (Goto et al.,
2010). Loss of heterozygosity analysis using
microsatellite markers specific to the FABP7 gene
revealed that 10 of 20 metastatic melanomas (and 0
of 14 primary melanomas) had undergone loss of
one FABP7 allele, leading the authors to postulate
that genomic instability that favors loss of FABP7
expression may lead to better prognosis.
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Neurological disorders
Note
FABP7 is overexpressed in the brains of Down
syndrome patients and has been postulated to
contribute
to
Down
syndrome-associated
neurological disorders (Sánchez-Font et al., 2003).
Pelsers et al. (2004) measured FABP7 levels in
various parts of the adult human brain, with a range
of 0,8 µg/g wet weight in the striatum and 3,1 µg/g
in the frontal lobe. Measurement of FABP7 and
FABP3 levels in the serum of patients with minor
brain injuries identified both these FABPs as more
sensitive at detecting brain injury than markers
currently in use for this purpose. Similarly, serum
FABP7 and FABP3 served as markers for
individuals who had undergone ischaemic stroke
(Wunderlich et al., 2005). FABP7 levels were also
elevated in the serum of patients with
neurodegenerative diseases such as Alzheimer's
disease, Parkinson's disease and other cognitive
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This article should be referenced as such:
De Rosa A, Pellegatta S, Rossi M, Tunici P, Magnoni L,
Speranza MC, Malusa F, Miragliotta V, Mori E, Finocchiaro
G, Bakker A.. A radial glia gene marker, fatty acid binding
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2014; 18(9):638-644.
644
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
GSTA1 (glutathione S-transferase alpha 1)
Ana Savic-Radojevic, Tanja Radic
Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Serbia
(ASR, TR)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/GSTA1ID40764ch6p12.html
DOI: 10.4267/2042/54029
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
genes (GSTA1, GSTA2, GSTA3, GSTA4, GSTA5)
and seven pseudogenes (Morel et al., 2002).
Review on GSTA1, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
Description
The GSTA1 gene is approximately 12 kb in length
and is closely flanked by other alpha class gene
sequences. The complete sequence of the 1,7-kb
intergenic region between exon 7 of an upstream
pseudogene and exon 1 of the GSTA1 gene has
been determined (Suzuki et al., 1993).
Identity
Other names: GST2, GSTA1-1, GTH1
HGNC (Hugo): GSTA1
Location: 6p12.2
Local order
Between the LOC647169 (similar to glutathione
transferase) and GSTA6P (glutathione S-transferase
alpha 6 pseudogene) (according to PubMed).
Note
The GSTA1 gene is composed of 7 exons spanning
a region of 12487 bases.
Transcription
The 1276-nucleotide transcript encodes a protein of
222 amino acid residues.
Pseudogene
An additional gene that encodes an uncharacterized
Alpha class GST has been identified. The protein
derived from this gene would have 19 amino acid
substitutions compared with the GSTA1 isoenzyme.
Several pseudogenes with single-base and/or
complete exon deletions have been identified, but
no reverse-transcribed pseudogenes have been
detected (Suzuki et al., 1993).
DNA/RNA
Note
The human alpha class genes are located in a cluster
on chromosome 6p12 and comprise five functional
GSTA1 gene. The GSTA1 gene spans a region of 12,5 kb composed of the seven exons (red) and six introns (green). Exons 1,
2, 3, 4, 5, 6 and 7 are 59 bp, 117 bp, 52 bp, 133 bp, 142 bp, 132 bp and 198 bp in length, respectively.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
645
GSTA1 (glutathione S-transferase alpha 1)
Savic-Radojevic A, Radic T
Crystal structure of human glutathione transferase (GST) A1-1 in complex with glutathione. Adapted from PDB (Grahn et
al., 2006).
Polymorphisms: GSTA1 has a functional three
apparently linked single nucleotide polymorphisms
(SNPs) in an SP1-responsive element within the
proximal promoter (G-52A, C-69T and T-567G),
plus at least four SNPs further upstream and a silent
SNP A-375G. Two variants, GSTA1*A (-567T, 69C,-52G) and GSTA1*B (-67G, -69T, -52A), have
been named according to the linked functional
SNPs. Specifically, these substitutions result in
differential expression with lower transcriptional
activation of variant GSTA1*B than common
GSTA1*A allele. It has been suggested that this
genetic variation can change an individual's
susceptibility to carcinogens and toxins, as well as,
affect the efficacy of some drugs (Coles and
Kadlubar, 2003). In addition, the linkage
disequilibrium between GSTA1*A/GSTA1*B and
GSTA2G335C (Ser112Thr) has been shown in
Caucasians: specifically, GSTA1*A/GSTA2C335
(Thr112) and GSTA1*B/GSTA2G335 (Ser112)
(Ning et al., 2004). It seems that the higher hepatic
expression of GSTA1 enzyme in homozygous
GSTA1 individuals is associated with the lower
hepatic expression of GSTA2 in GSTA2C335
(Thr112) individuals (Coles et al., 2001a; Ning et
al., 2004). Other haplotypes within this
nomenclature but including SNPs C-115T, T-631G,
and C-1142G also have been proposed
(Bredschneider et al., 2002; Guy et al., 2004).
Polymorphisms upstream of G-52C seem to have
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
little effect on GSTA1 expression (Morel et al.,
2002).
Protein
Note
Glutathione S-transferase A1 is N-terminally
processed.
Amino acids: 222.
Calculated molecular mass: 25,63 kDa.
Description
The active GSTA1-1 enzyme is a homodimer, with
each subunit containing a GSH-binding site (G-site)
and a second adjacent hydrophobic binding site for
the electrophilic substrate (H-site) (Wilce and
Parker, 1994).
The C-terminal region of GSTA1-1 contributes to
the catalytic and noncatalytic ligand-binding
functions of the enzyme, while the conserved G-site
is located in the N-terminal domain (Balogh et al.,
2009).
Protein flexibility and dynamics in a molten
globule-active site including the C-terminal α9
helix and the protruding ends of the α4-α5 helices
result in achieving remarkable catalytic promiscuity
of GSTA1-1 (Wu and Dong, 2012; Honaker et al.,
2013). It has been proposed that the α9 helix may
function as a mobile gate to the active-site cavity,
controlling substrate access and product release.
646
GSTA1 (glutathione S-transferase alpha 1)
Savic-Radojevic A, Radic T
Structure determination and refinement of human alpha class glutathione transferase A1-1, and a comparison with the
MU and PI class enzymes. Adapted from PDB (Sinning et al., 1993).
Expression
Function
GSTA1-1 is highly expressed (as mRNA and
protein) in liver, intestine, kidney, adrenal gland,
pancreas and testis, while expression in a wide
range of tissues is low (Hayes and Pulford, 1995;
Coles et al., 2001a). Both positive and negative
regulatory regions are present in the 5` noncoding
region of GSTA1, including a polymorphic SP1binding site within the proximal promoter. Binding
of the transcription factor AP1 has been suggested
as a common mechanism for up-regulation of GSTs
(Hayes and Pulford, 1995). The results of recent
study also implied the role of a Kelch-like ECHassociated protein 1 (Keap1)-dependent signaling
pathway for the induction of the constitutive
GSTA1 expression during epithelial cell
differentiation (Kusano et al., 2008). Regarding
GSH-dependent ∆5-∆4 isomerase activity of this
class of enzyme, it has been shown that
steroidogenic factor 1 (SF-1) is involved in
regulation of expression of GSTA genes
(Matsumura et al., 2013). Aberrant overexpression
has been observed in various malignancies such as
colorectal (Hengstler et al., 1998) and lung cancer
(Carmichael et al., 1988), while decrease in alpha
class GSTs has been observed in stomach and liver
tumors (Howie et al., 1990). A detailed recent
review on GSTA1 can be found in Wu and Dong,
2012.
Human GSTA1-1 enzyme catalyzes the GSHdependent detoxification of electrophiles showing
highly promiscuous substrate selectivity for many
structurally
unrelated
chemicals,
including
environmental carcinogens (e.g. benzo(a)pyrene
diol epoxides), several alkylating chemotherapeutic
agents (such as busulfan, chlorambucil, melphalan,
phosphoramide
mustard,
cyclophosphamide,
thiotepa), as well as, steroids and products of lipid
degradation. GSTA1-1 is the most highly expressed
GST of the liver and could therefore, be critical for
"systemic"
detoxification
of
electrophilic
xenobiotics including carcinogens and drugs (Coles
and Kadlubar, 2005).
In addition to enzymatic detoxification, GSTA1
acts as modulator of mitogen-activated protein
kinase (MAPK) signal transduction pathway via a
mechanism involving protein-protein interactions.
Namely, GSTA1 forms complexes with c-Jun Nterminal kinase (JNK), modifying JNK activation
during cellular stress (Adnan et al., 2012).
Thus, it is possible that GSTA1 confer drug
resistance by two distinct means: by direct
inactivation (detoxification) of chemotherapeutic
drugs and by acting as inhibitors of MAPK
pathway.
Localisation
The alpha class GSTs is showing strong intra-class
sequence similarity (Balogh et al., 2009).
Homology
Cytosolic.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
647
GSTA1 (glutathione S-transferase alpha 1)
Savic-Radojevic A, Radic T
from acute myeloid leukemia patients, showing
resistance to doxorubicin in vitro (Sargent et al.,
1999). In addition, GSTA1 and CYP39A1 (member
of cytochrome P450 family) polymorphisms were
found to be associated with pharmacokinetics of
busulfan, which is used in preparative regimens
prior to stem cell transplantation in pediatric
patients (ten Brink et al., 2013).
Mutations
Germinal
None described so far.
Somatic
36 mutations (COSMIC): 26 substitution-missense,
4 substitution-nonsense, 5 substitution-coding
silent, 1 unknown type.
Prostate cancer
Note
Genetic variants of GSTA1 and GSTT1 may
modify prostate cancer risk, especially among
smokers (Komiya et al., 2005).
Implicated in
Colorectal cancer
Note
Regarding the role of GSTA1 polymorphism in the
risk of colorectal cancer, the results of
epidemiological studies are still inconclusive.
Several studies showed that GSTA1*B genotype
(low hepatic expression) is associated with
increased susceptibility to colorectal cancer, which
imply the possible inefficient hepatic detoxification
of food-derived carcinogen metabolite N-acetoxyPhIP (Coles et al., 2001b; Sweeney et al., 2002). In
contrast,
meta-analysis
of
Economopoulos
representing the pooled analysis of four studies
(1648 cases, 2039 controls) does not confer this
association.
Asthma
Note
Genetic alterations in GST enzymes may influence
the detoxification of environmental toxic
substances in airway and increase the risk of
asthma.
Thus, it has been shown that subjects with at least
one allele -69T in the GSTA1 genotype have an
increased risk of asthma (Polimanti et al., 2010).
References
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Breast cancer
Note
The role of GSTA1 polymorphism in breast cancer
risk was mainly based on investigation on response
to chemotherapeutic drugs in these patients. In
breast cancer patients on cyclophosphamide
containing chemotherapy carriers of GSTA1*B/*B
genotype showed significantly reduced five years
risk of death in comparison to GSTA1*A
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Note
Recent investigation indicates that the GSTA1-low
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bladder cancer in smokers (Matic et al., 2013). In
addition, it seems that GSTA1 polymorphism may
influence vulnerability to oxidative DNA damage,
thereby contributing to the malignant potential of
transitional cell carcinoma (Savic-Radojevic et al.,
2013).
Wilce MC, Parker MW. Structure and function of
glutathione S-transferases. Biochim Biophys Acta. 1994
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Hayes JD, Pulford DJ. The glutathione S-transferase
supergene family: regulation of GST and the contribution
of the isoenzymes to cancer chemoprotection and drug
resistance. Crit Rev Biochem Mol Biol. 1995;30(6):445-600
Hengstler JG, Böttger T, Tanner B, Dietrich B, Henrich M,
Knapstein PG, Junginger T, Oesch F. Resistance factors
in colon cancer tissue and the adjacent normal colon
tissue: glutathione S-transferases alpha and pi, glutathione
and aldehyde dehydrogenase. Cancer Lett. 1998 Jun
5;128(1):105-12
Myeloid leukemia
Note
Aberant overexpression of both GSTA1 and
GSTA2 proteins was found in blast cells derived
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E, Nishida M, Kurose H, Itoh K, Kobayashi A, Yamamoto
M, Uchida K. Keap1 regulates the constitutive expression
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Pharmacogenetics. 2001a Nov;11(8):663-9
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Eichelbaum M, Nüssler AK, Neuhaus P, Zanger UM,
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on glutathione S-transferase A1 (GSTA1): c-Jun Nterminal kinase (JNK) complex dissociation in human
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human glutathione transferase alpha locus: genomic
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characterization of the genetic polymorphism in the
hGSTA1
promoter.
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Wu B, Dong D. Human cytosolic glutathione transferases:
structure, function, and drug discovery. Trends Pharmacol
Sci. 2012 Dec;33(12):656-68
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Novel markers of susceptibility to carcinogens in diet:
associations with colorectal cancer. Toxicology. 2002 Dec
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WM. Enzymatic detoxication, conformational selection, and
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D, Krivic B, Suvakov S, Savic-Radojevic A, PljesaErcegovac M, Tulic C, Coric V, Simic T. GSTA1, GSTM1,
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LF, Kadlubar FF, Coles BF. Association between a
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Human glutathione S-transferase A (GSTA) family genes
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This article should be referenced as such:
Grahn E, Novotny M, Jakobsson E, Gustafsson A, Grehn
L, Olin B, Madsen D, Wahlberg M, Mannervik B, Kleywegt
GJ. New crystal structures of human glutathione
transferase A1-1 shed light on glutathione binding and the
conformation of the C-terminal helix. Acta Crystallogr D
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Savic-Radojevic A, Radic T. GSTA1 (glutathione Stransferase alpha 1). Atlas Genet Cytogenet Oncol
Haematol. 2014; 18(9):645-649.
649
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
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Gene Section
Short Communication
MOAP1 (Modulator Of Apoptosis 1)
Gamze Ayaz, Mesut Muyan
Department of Biological Sciences, Middle East Technical University, Ankara, Turkey (GA, MM)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/MOAP1ID46494ch14q32.html
DOI: 10.4267/2042/54030
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Protein
Short communication on MOAP1, with data on
DNA/RNA, on the protein encoded and where the
gene is implicated.
Note
MOAP1 is a short-lived protein with a half-life of
25 minutes.
It is degraded by the ubiquitin-proteosome system
(Fu et al., 2007).
Identity
Description
Other names: MAP-1, PNMA4
HGNC (Hugo): MOAP1
Location: 14q32.12
MOAP-1 is a 351 amino-acid long protein with a
molecular mass of 39.5 kDa.
Isoelectric point (pI) of MOAP-1 is 4.939 at pH 7.0.
MOAP-1 contains a BH3 (Bcl-2 homology 3) like
domain required for homodimerization and
interaction with Bcl-2 associated X (Bax) protein.
Under normal condition, MOAP1 is held as an
inactive conformation through intramolecular
interactions. Interaction between RASSF1A (rasassociation domain family 1, isoform A) and
MOAP1 reduces the inhibitory intramolecular
interaction of MOAP1 and allows MOAP1 through
the BH3 like domain to bind Bax (Baksh et al.,
2005).
DNA/RNA
Description
Human MOAP1 gene contains three exons and the
encoding sequence of 1056 bases is in the exon 3.
Transcription
MOAP1 is a 351 amino-acid long protein.
Pseudogene
No reported pseudogenes.
The MOAP1 gene is located in the reverse strand. Exons are shown as boxes and introns as lines. The filled box in the exon
3 is the coding sequence of MOAP1. Numbers below represent the size of exon or intron in base pair.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
650
MOAP1 (Modulator Of Apoptosis 1)
Ayaz G, Muyan M
the downregulation of MOAP1 expression and the
aggressiveness of breast cancer (Law, 2012).
Expression
MOAP1 is expressed in the adipose, adrenal, blood,
brain, breast, colon and heart. MOAP1 is expressed
in higher level in the heart and brain.
To be noted
Note
miRNA: It is reported that miR-1228 prevents
cellular apoptosis by binding to the 3'UTR of
MOAP1 mRNA, thereby decreasing MOAP-1
protein levels (Yan and Zhao, 2012).
Localisation
MOAP-1 protein localizes in the cytoplasm (Law,
2012) and also seen in the mitochondria (Tan et al.,
2005).
Function
References
MOAP1 is a BH3-like protein that acts as a proapoptotic molecule (Tan et al., 2001). When
overexpressed, MOAP1 induces caspase-dependent
apoptosis in mammalian cells (Tan et al., 2005).
Studies showed that TNFα stimulation recruits
RASSF1A and MOAP1 to death receptors
complexes. This recruitment leads to the
association of RASSF1A with MOAP1 and to the
induction of a conformational change in MOAP1.
This results in the opening of the BH3 domain to
allow MOAP1 to interact with Bax. Bax is
subsequently inserted into the mitochondrial
membrane leading to apoptosis (Baksh et al., 2005;
Foley et al., 2008).
Tan KO, Tan KM, Chan SL, Yee KS, Bevort M, Ang KC,
Yu VC. MAP-1, a novel proapoptotic protein containing a
BH3-like motif that associates with Bax through its Bcl-2
homology domains. J Biol Chem. 2001 Jan
26;276(4):2802-7
Baksh S, Tommasi S, Fenton S, Yu VC, Martins LM,
Pfeifer GP, Latif F, Downward J, Neel BG. The tumor
suppressor RASSF1A and MAP-1 link death receptor
signaling to Bax conformational change and cell death. Mol
Cell. 2005 Jun 10;18(6):637-50
Tan KO, Fu NY, Sukumaran SK, Chan SL, Kang JH, Poon
KL, Chen BS, Yu VC. MAP-1 is a mitochondrial effector of
Bax. Proc Natl Acad Sci U S A. 2005 Oct
11;102(41):14623-8
Fu NY, Sukumaran SK, Yu VC. Inhibition of ubiquitinmediated degradation of MOAP-1 by apoptotic stimuli
promotes Bax function in mitochondria. Proc Natl Acad Sci
U S A. 2007 Jun 12;104(24):10051-6
Homology
Also highly conserved in rat (Rattus norvegicus)
and mouse (Mus musculus), human MOAP1
protein shares 99% amino acids identity with that of
chimpanzee (Pan troglodytes) (Law et al., 2012).
Foley CJ, Freedman H, Choo SL, Onyskiw C, Fu NY, Yu
VC, Tuszynski J, Pratt JC, Baksh S. Dynamics of
RASSF1A/MOAP-1 association with death receptors. Mol
Cell Biol. 2008 Jul;28(14):4520-35
Mutations
Law J.. MOAP1: A Candidate Tumor Suppressor Protein
Master Thesis, University of Alberta, Canada, 2012
http://hdl.handle.net/10402/era.24828.
Note
Gene mutations have not been described yet.
Law J, Yu VC, Baksh S.. Modulator of Apoptosis 1: A
Highly Regulated RASSF1A-Interacting BH3-Like Protein.
Mol
Biol
Int.
2012;2012:536802.
doi:
10.1155/2012/536802. Epub 2012 Jun 14.
Implicated in
Breast cancer
Yan B, Zhao JL.. miR-1228 prevents cellular apoptosis
through targeting of MOAP1 protein. Apoptosis. 2012
Jul;17(7):717-24. doi: 10.1007/s10495-012-0710-9.
Disease
Microarray analysis of 176 primary, treatmentnaive breast cancer and of 10 normal breast tissue
samples suggests that the MOAP1 gene expression
is significantly down-regulated in breast cancer. It
appears that there is a positive correlation between
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
This article should be referenced as such:
Ayaz G, Muyan M. MOAP1 (Modulator Of Apoptosis 1).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9):650651.
651
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Short Communication
PHLDA1 (pleckstrin homology-like domain,
family A, member 1)
Maria Aparecida Nagai
Discipline of Oncology, Department of Radiology and Oncology, Medical School, University of Sao
Paulo, Center for Translational Investigation in Oncology, Cancer Institute from Sao Paulo State, Sao
Paulo, Brazil (MAN)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/PHLDA1ID41707ch12q15.html
DOI: 10.4267/2042/54031
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PHLDA1 protein has a modular structure
containing a central pleckstrin homology-like
domain (PHL) and prolin-glutamine (PQ) and
proline-histidine (PH) repeats in the C-terminal
region (see figure above).
Abstract
Short communication on PHLDA1, with data on
DNA/RNA, on the protein encoded and where the
gene is implicated.
Expression
Identity
DNA/RNA
PHLDA1 is widely expressed in mammalian tissues
displaying cytoplasmic, vesicle membrane, plasma
membrane and nuclear subcellular localization.
PHLDA1 expression is up-regulated by estrogen,
IGF-1 (insulin-like growth factor 1), FGF
(fibroblast growth factor), TPA (phorbol ester), and
ER (endoplamic reticulum)-stress agents such as
homocysteine, tunicamicyne, and farnesol.
Description
Localisation
PHLDA1 gene contains 2 exons, 1 intervening
sequence and spans 6,3 kb of genomic DNA.
Cytoplasm, vesicle membrane, plasma membrane,
nucleus.
Transcription
Function
1,2 kb mRNA.
Protein binding. Several evidences have implicate
PHLDA1 as a potential transcriptional activator that
acts as a pro-apoptotic and antiproliferative factor,
however the mechanisms by which PHLDA1
mediates cell survival is still under investigation.
Other names: DT1P1B11, PHRIP, TDAG51
HGNC (Hugo): PHLDA1
Location: 12q21.2
Local order: Minus strand.
Pseudogene
Not identified.
Protein
Homology
Description
PHLDA2 (pleckstrin homology-like domain, family
A, member 2) and PHLDA3 (pleckstrin homologylike domain, family A, member 3) are paralogs for
PHLDA1.
The PHLDA1 gene encodes for a 401 amino acid
protein that is a member of the evolutionarily
conserved pleckstrin homology-like domain family.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
652
PHLDA1 (pleckstrin homology-like domain, family A, member 1)
Nagai MA
Schematic representation of the modular structure of PHLDA1 protein. PHL: pleckstrin homology-like domain spanning
amino acids residues from 150 to 283; QQ: proline/glutamine rich sequence (aa residues from 189 to 204); PQ: prolineglutamine tracts (aa residues from 311 to 346); PH: proline-histidine-rich tracts (aa residues from 352 to 389); *: indicates
phosphorylation sites.
significantly better in patients with tumors that
were negative for PHLDA1, and a multivariate
analysis suggested that PHLDA1 is an independent
prognostic factor in OSCC patients (CoutinhoCamillo et al., 2013).
Mutations
Note
Short genetic variation - dbSNP: rs139162669,
rs73385441,
rs74620794,
rs147230079,
rs76437300,
rs186978611,
rs140610935,
rs144470255, rs79545253, rs147644129.
Colon cancer
Note
Altered PHLDA1 expression has been shown to be
associated with the process of intestinal
tumorigenesis (Sakthianandeswaren et al., 2011).
Implicated in
Melanoma
Note
PHLDA1 expression was associated with reduced
cell growth and colony formation and with
increased apoptotic rates and drug sensitivity in
melanoma cell lines. Loss of PHLDA1 has been
correlated with melanoma progression (Neef et al.,
2002).
Basal cell carcinoma
Breast cancer
Atherosclerosis
Note
Down-regulation of PHLDA1 mRNA and protein
expression is frequently observed in primary
invasive breast tumours.
Down-regulation of PHLDA1 protein has been
shown to be a strong predictor of poor prognosis for
breast cancer patients, indicating that reduced
PHLDA1 expression contribute for breast cancer
progression and might serve as useful prognostic
biomarker of disease outcome (Nagai et al., 2007).
Note
In vivo and in vitro studies demonstrated that
increased PHLDA1 expression induced by
homocysteine
promotes
detachment-mediated
programmed cell death and contributes to the
development of atherosclerosis (Hossain et al.,
2003).
Genetic variant in an intergenic region of the
PHLDA1 gene (rs2367446) has been shown to be
associated with the development of cardiovascular
diseases (Hossain et al., 2013).
Note
PHLDA1 has also been shown to be a follicular and
epithelial stem cell marker (Ohyama et al., 2006;
Sakthianandeswaren et al., 2011) with potential to
differentiates between trichoepithelioma and basal
cell carcinoma (Sellheyer and Nelson, 2011).
Oral cancer
Epilepsy
Note
Reduced expression of PHLDA1 was observed in
60,7% of oral squamous cell carcinomas (OSCC),
especially in well-differentiated tumors.
Positive PHLDA1 immunostaining was associated
with advanced clinical stages of the disease,
suggesting that PHLDA1 has a functional role in
oral tumorigenesis.
Overall and disease-free survival rates were
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Note
PHLDA1 expression has been shown to be higher
in the anterior temporal neocortex from patients
with intractable epilepsy when compared with the
levels observed in the neocortex from the control
group, suggesting a possible association of
PHLDA1 in the physiopathology of the disease (Xi
et al., 2007).
653
PHLDA1 (pleckstrin homology-like domain, family A, member 1)Nagai MA
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the human PHLDA1/TDAG51 gene: down-regulation in
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(TDAG51) is superior to cytokeratin-20 in differentiating
between trichoepithelioma and basal cell carcinoma in
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Hossain GS, van Thienen JV, Werstuck GH, Zhou J, Sood
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FA. Down-regulation of PHLDA1 gene expression is
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654
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
ADAMTS15 (ADAM Metallopeptidase With
Thrombospondin Type 1 Motif, 15)
Santiago Cal, Alvaro J Obaya
Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia (IUOPA),
Universidad de Oviedo, 33006, Asturias, Spain (SC), Biologia Funcional, Instituto Universitario de
Oncologia (IUOPA), Universidad de Oviedo, 33006, Asturias, Spain (AJO)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAMTS15ID45587ch11q24.html
DOI: 10.4267/2042/54032
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
8 exons, spans approximately 27.66 Kb of genomic
DNA in the centromere-to-telomere orientation.
The translation initiation codon is located to exon 1,
and the stop codon to exon 8.
protein, with an estimated molecular weight of
103,2 kDa. ADAMTS-15 shares a structural
multidomain complex architecture with the rest of
the members of the ADAMTS family.
This organization includes a signal peptide, a
prodomain involved in maintaining enzyme latency
and a catalytic domain that contains the consensus
sequence HEXXHGXXHD involved in the
coordination of the zinc atom necessary for
catalytic activiy of the enzyme.
This sequence ends in an Asp residue which
distinguishes
ADAMTSs
from
other
metalloproteases such as MMPs. Following this
catalytic region there are several other domains
characterized as disintegrin-like domain, a central
thrombospondin-1 (TSP-1) motif, a cysteine-rich
domain, a spacer region and two more TSP-1
domains (Cal et al., 2002).
Protein
Expression
Abstract
Review on ADAMTS15, with data on DNA/RNA,
on the protein encoded and where the gene is
implicated.
Identity
HGNC (Hugo): ADAMTS15
Location: 11q24.3
DNA/RNA
Description
ADAMTS15 cDNA was originally cloned from
both, a human liver and kidney fetal cDNA library
(Cal et al., 2002).
Description
The open reading fame encodes a 950 amino acid
Domain organization of ADAMTS-15. Pro: prodomain; TSP: thrombospondin type-1 domains.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
655
ADAMTS15 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 15)
Later on, in the search for proteinases and
proteinase inhibitors in articular cartilage from
femoral heads of patients with end-stage
osteoarthritis (OA) Kevorkian et al. found high
levels of ADAMTS-15 expression in samples from
both, OA patients as well as normal controls
(Kevorkian et al., 2004). In relation with
ADAMTS-15 participation in tumor progression its
expression has been described in either normal cells
or cells adjacent or marginal to cancer tissue in
samples from colon adenocarcinoma as well as in
samples from head and neck squamous cell
carcinoma (Viloria et al., 2009; Stokes et al., 2010).
Additionally ADAMTS-15 presence has also been
detected in some breast and prostate cancer cell
lines (Molokwu et al., 2010).
chicken (Refseq: XM_417874), and zebrafish
(Refseq: XM_001341842).
Mutations
Somatic
ADAMTS15 was identified as one of the so-called
CAN genes found to be mutated in a small set of
colorectal cancers (Sjöblom et al., 2006). Two
heterozigous somatic mutations were described out
of eleven human cancer samples (cDNA:
2309A>G, cDNA: 2632T>G). Functional relevance
of mutations found in colorectal cancer were
described for a deleterious single base mutation
24544∆G affecting the two carboxy-terminal
thrombospondin motifs of ADAMTS-15 (Viloria et
al., 2009). The derived truncated form of
ADAMTS-15 (ADAMTS15_G849fs) is barely
found in the pericellular space of the cell being
mostly liberated to the culture media. Functional
studies revealed ADAMTS15_G849fs not showing
the anti-tumoral properties of full length
ADAMTS-15. In the same study, three other
mutations where identified, a base pair mutation
affecting the second TSP-1 domain (24616C>T), a
silent base pair change (13777C>T) and another
base deletion generating a completely truncated
form of ADAMTS-15 (366∆) (Viloria et al., 2009).
Localisation
Extracellular, mostly pericellular.
Function
Few studies describe ADAMTS-15 function
beyond those describing its participation in cancer
and osteoartritic processes. Regarding cancer,
ADAMTS-15 has recently emerged as a putative
tumor suppresor gene since it is downregulated in
breast cancer, and functionally inactivated through
specific mutations in colorectal cancer (Porter et al.,
2004; Porter et al., 2006; Viloria et al., 2009). In
addition, aberrant expression of ADAMTS-15 is
implicated in prostate cancer progression
(Molokwu et al., 2010). The latest apparently
results from the relationship between ADAMTS-15
expression and versican degradation. Thus,
ADAMTS-15 seems to be acting as a versicandegrading enzyme whose accumulation potentially
contributes to prostate cancer pathology (Cross et
al., 2005). In this regard, versican seems to be one
of the targets of ADAMTS-15 proteolityc activity
which involves this protein in processes such as
cancer or skeletal muscle fiber formation (Croos et
al., 2005; Stupka et al., 2013; Dancevic et al.,
2013).
Implicated in
Various cancers
Note
ADAMTS-15 has recently emerged as a putative
tumor suppresor gene since it is downregulated in
breast cancer, and functionally inactivated through
specific mutations in colorectal cancer (Porter et al.,
2006; López-Otín et al., 2009; Viloria et al., 2009).
In addition, aberrant expression of ADAMTS-15 is
implicated in prostate cancer progression (Cross et
al., 2005; Molokwu et al., 2010). The first
indication regarding a potential protective role for
ADAMTS15 derived from the observation that low
ADAMTS15 expression levels coupled to high
ADAMTS8 levels conferred poor prognosis to
breast cancer patients (Porter et al., 2006).
Moreover, ADAMTS15 was identified as one of the
so-called CAN genes found to be mutated in a
small set of colorectal cancers (Sjöblom et al.,
2006). Functional support to the putative relevance
of ADAMTS-15 as a tumor suppresor protease was
described after finding four additional mutations in
ADAMTS-15 gene sequence in human colon
carcinomas (Viloria et al., 2009). Two of the new
mutations resulted in the generation of truncated
forms of ADAMTS-15, one of them lacking the last
two thrombospondin domains whereas the other
originating a complete ADAMTS-15 knock-down.
Homology
ADAMTS-15 belongs to the A Disintegrin And
Metalloprotease Domains with ThromboSpondin
motifs (ADAMTS) family, which consists of 19
secreted zinc metalloproteinases (Porter et al.,
2005). All members of the family share the same
structural domain design. ADAMTS-15 is, among
all the members, closely related to ADAMTS-1
which suggested its involvement in angiogenic
processes (Cal et al., 2002).
The ADAMTS15 gene is conserved in chimpanzee
(Refseq:
XM_522253),
macaque
(Refseq:
XM_001113698), dog (Refseq: XM_005620295),
cow (Refseq: NM_001192390), mouse (Refseq:
NM_001024139), rat (Refseq: NM_001106810),
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Cal S, Obaya AJ
656
ADAMTS15 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 15)
Cal S, Obaya AJ
Functional analysis revealed that the presence of the
two last thrombospondin domains is important for
the pericellular loacalization of ADAMTS-15 and
affects the anti-tumoral function of full length
ADAMTS-15 (Viloria et al., 2009; Dancevic et al.,
2013).
More recently, ADAMTS-15 has been described as
a head and neck squamous cell carcinoma
(HNSCC)-associated proteinase since its expression
is elevated (together with ADAMTS-1 and
ADAMTS-8) in areas surrounding HNSCC tumor
microenvironment (Demircan et al., 2009; Stokes et
al., 2010).
In addition, these three members of the ADAMTS
family have elevated expression levels in HNSCC
tumor versus normal tissue and in HNSCC derived
cell lines vs normal keratinocytes (Stokes et al.,
2010).
ADAMTS-15 has also been indirectly involved in
androgen-mediated prostate cancer growth and
proliferation, function that depends on ADAMTS15 versicanolytic activity (Cross et al., 2005;
Molokwu et al., 2010).
Molokwu et al identified one androgen-responsive
element (ARE) in ADAMTS-15 promoter and 12
more AREs in its gene sequence. In the same article
the authors demonstrated ADAMTS-15 reduction
both, at mRNA and protein levels, in the presence
of dihidrotestorone (DHT).
ADAMTS-15 down-regulation in prostate cancer
resulted in high versican levels which is a poor
prognosis indicator in these type of tumors
(Ricciardelli et al., 1998; Luo et al., 2002;
Molokwu et al., 2010).
Breast cancer
Colon cancer
Porter S, Clark IM, Kevorkian L, Edwards DR. The
ADAMTS metalloproteinases. Biochem J. 2005 Feb
15;386(Pt 1):15-27
Note
ADAMTS15 elevated expression correlates with
favorable outcome in patients with breast cancer
(Porter et al., 2006).
References
Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul
K, Marshall VR, Horsfall DJ. Elevated levels of versican
but not decorin predict disease progression in early-stage
prostate cancer. Clin Cancer Res. 1998 Apr;4(4):963-71
Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V,
López-Otín C. Cloning, expression analysis, and structural
characterization of seven novel human ADAMTSs, a family
of metalloproteinases with disintegrin and thrombospondin1 domains. Gene. 2002 Jan 23;283(1-2):49-62
Luo J, Dunn T, Ewing C, Sauvageot J, Chen Y, Trent J,
Isaacs W. Gene expression signature of benign prostatic
hyperplasia revealed by cDNA microarray analysis.
Prostate. 2002 May 15;51(3):189-200
Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone
L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark
IM. Expression profiling of metalloproteinases and their
inhibitors in cartilage. Arthritis Rheum. 2004 Jan;50(1):13141
Porter S, Scott SD, Sassoon EM, Williams MR, Jones JL,
Girling AC, Ball RY, Edwards DR. Dysregulated
expression of adamalysin-thrombospondin genes in
human breast carcinoma. Clin Cancer Res. 2004 Apr
1;10(7):2429-40
Cross NA, Chandrasekharan S, Jokonya N, Fowles A,
Hamdy FC, Buttle DJ, Eaton CL. The expression and
regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3
by TGFbeta1 in prostate cells: relevance to the
accumulation of versican. Prostate. 2005 May
15;63(3):269-75
Note
ADAMTS15 expression inversely correlates with
histopathologic differentiation grade in human
colorectal carcinomas when analyzing ADAMTS15 inmunostaining in normal colon epithelia, welldifferentiated tumors, moderately differentiated
tumors, and poorly differentiated colorectal
carcinomas (Viloria et al., 2009).
Porter S, Span PN, Sweep FC, Tjan-Heijnen VC,
Pennington CJ, Pedersen TX, Johnsen M, Lund LR,
Rømer J, Edwards DR. ADAMTS8 and ADAMTS15
expression predicts survival in human breast carcinoma.
Int J Cancer. 2006 Mar 1;118(5):1241-7
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,
Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu
C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N,
Vogelstein B, Kinzler KW, Velculescu VE. The consensus
coding sequences of human breast and colorectal cancers.
Science. 2006 Oct 13;314(5797):268-74
Head and neck squamous carcinoma
(HNSCC)
Note
ADAMTS15 mRNA levels, together with those of
other
ADAMTS
members
(ADAMTS1,
ADAMTS4,
ADAMTS5,
ADAMTS8,
ADAMTS9), were reduced in HNSCC primary
tumors compared with paired non-cancerous tissues
(Demircan et al., 2009). Regarding tumor
microenvironment ADAMTS15 expression is
elevated in adjacent and margin tissue when
compared with tumor center tissue (Stokes et al.,
2010).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Demircan K, Gunduz E, Gunduz M, Beder LB, Hirohata S,
Nagatsuka H, Cengiz B, Cilek MZ, Yamanaka N, Shimizu
K, Ninomiya Y. Increased mRNA expression of ADAMTS
metalloproteinases in metastatic foci of head and neck
cancer. Head Neck. 2009 Jun;31(6):793-801
López-Otín C, Palavalli LH, Samuels Y. Protective roles of
matrix metalloproteinases: from mouse models to human
cancer. Cell Cycle. 2009 Nov 15;8(22):3657-62
Viloria CG, Obaya AJ, Moncada-Pazos A, Llamazares M,
Astudillo A, Capellá G, Cal S, López-Otín C. Genetic
657
ADAMTS15 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif, 15)
inactivation of ADAMTS15 metalloprotease in human
colorectal cancer. Cancer Res. 2009 Jun 1;69(11):4926-34
disintegrin-like and metalloproteinase domain with
thrombospondin-1 repeats-15: a novel versican-cleaving
proteoglycanase.
J
Biol
Chem.
2013
Dec
27;288(52):37267-76
Molokwu CN, Adeniji OO, Chandrasekharan S, Hamdy FC,
Buttle DJ. Androgen regulates ADAMTS15 gene
expression in prostate cancer cells. Cancer Invest. 2010
Aug;28(7):698-710
Stupka N, Kintakas C, White JD, Fraser FW, Hanciu M,
Aramaki-Hattori N, Martin S, Coles C, Collier F, Ward AC,
Apte SS, McCulloch DR. Versican processing by a
disintegrin-like and metalloproteinase domain with
thrombospondin-1 repeats proteinases-5 and -15 facilitates
myoblast fusion. J Biol Chem. 2013 Jan 18;288(3):1907-17
Stokes A, Joutsa J, Ala-Aho R, Pitchers M, Pennington CJ,
Martin C, Premachandra DJ, Okada Y, Peltonen J,
Grénman R, James HA, Edwards DR, Kähäri VM.
Expression profiles and clinical correlations of degradome
components in the tumor microenvironment of head and
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1;16(7):2022-35
This article should be referenced as such:
Cal S, Obaya AJ. ADAMTS15 (ADAM Metallopeptidase
With Thrombospondin Type 1 Motif, 15). Atlas Genet
Cytogenet Oncol Haematol. 2014; 18(9):655-658.
Dancevic CM, Fraser FW, Smith AD, Stupka N, Ward AC,
McCulloch DR. Biosynthesis and expression of a
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Cal S, Obaya AJ
658
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
ADRB2 (adrenoceptor beta 2, surface)
Denise Tostes Oliveira, Diego Mauricio Bravo-Calderón
Department of Stomatology, Area of Pathology, Bauru School of Dentistry - University of Sao Paulo,
Bauru, Brazil (DTO, DMBC)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/ADRB2ID43818ch5q32.html
DOI: 10.4267/2042/54033
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
2006). The receptor is comprised of 413 amino acid
residues of approximately 46500 daltons (Johnson,
2006). β2 adrenergic receptor is N-glycosylated at
amino acids 6, 15, and 187; these are important for
roper insertion of the receptor into the membrane as
well as for agonist trafficking (McGraw and
Liggett, 2005; Johnson, 2006).
Abstract
Review on ADRB2, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Identity
Expression
Other names: ADRB2R, ADRBR, B2AR, BAR,
BETA2AR
HGNC (Hugo): ADRB2
Location: 5q32
β2 adrenergic receptor is widely distributed, this
protein is expressed by airway smooth muscle (3040000 per cell), epithelial and endothelial cells of
the lung, smooth muscle of blood vessels, skeletal
muscle, mast cells, lymphocytes, oral and skin
keratinocytes and also by diverse cancer cells
(Kohm and Sanders, 2001; Lutgendorf et al., 2003;
Johnson, 2006; Sood et al., 2006; Thaker et al.,
2006; Yang et al., 2006; Sastry et al., 2007; Yu et
al., 2007; Liu et al., 2008a; Liu et al., 2008b; Shang
et al., 2009; Sivamani et al., 2009; Yang et al.,
2009; Bernabé et al., 2011; Bravo-Calderón et al.,
2011-2012; Steenhuis et al., 2011; Zhang et al.,
2011; Loenneke et al., 2012).
DNA/RNA
Description
ADBR2 gene spans about 2,04 kb and consists of
one exon.
Transcription
ADBR2 no has introns in either their coding or
untranslated sequences. The primary transcripts are
processed at their 5' and 3' ends like other
premessenger RNAs, but no splicing is needed.
Localisation
Pseudogene
β2 adrenergic receptor is a transmembrane protein.
Like all GPCRs, the β2 adrenergic receptor has
seven transmembrane a domains that form a pocket
containing binding sites for agonists and
competitive antagonists (McGraw and Liggett,
2005; Johnson, 2006). There are 3 extracellular
loops, with one being the amino terminus, and 3
intracellular loops, with a carboxy terminus
(McGraw and Liggett, 2005; Johnson, 2006).
No pseudogenes have been reported.
Protein
Description
β2 adrenergic receptor is a member of the
superfamily of G-protein coupled receptors
(GPCRs) (McGraw and Liggett, 2005; Johnson,
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
659
ADRB2 (adrenoceptor beta 2, surface)
Oliveira DT, Bravo-Calderón DM
Activation of protein kinase A (PKA) by signal transduction of β2 adrenergic receptor (adapted of Rosenbaum et al., 2009).
foradrenergic receptors in these experimental
effects.
Norepinephrine was later found to increase the in
vitro invasive potential of ovarian cancer cells, an
effect that was blocked by propranolol (Sood et al.,
2006). Norepinephrine also increased tumor cell
expression of matrix metalloproteinase-2 (MMP-2)
and MMP-9, and pharmacologic blockade of
MMPs abrogated the effects of norepinephrine on
tumor cell invasive potential (Sood et al., 2006).
In the same way, Thaker et al. (Thaker et al., 2006)
correlated chronic behavioral stress with higher
levels of tissue catecholamines and more invasive
growth of ovarian carcinoma cells in an orthotopic
mouse model. These effects were mediated through
β2 adrenergic receptor activation of PKA signaling
pathway (Thaker et al., 2006). Tumors in stressed
animals showed increased vascularization and
enhanced expression of VEGF, MMP2 and MMP9;
these effects could be abrogated by propranolol
(Thaker et al., 2006).
Function
Agonist binding of β2 adrenergic receptor results in
activation of Gs protein. The Gs protein a subunit
stimulates adenylyl cyclase to generate cyclic 3'-5'adenosine monophosphate (cAMP), which in
sequence activates the cAMP-dependent protein
kinase A (PKA) and the agonist-occupied receptor
is phosphorylated.
After phosphorylation, the receptor switches its
coupling specificity to Gi. GTP-bound Giα
dissociates from the heterodimeric Gβγ, and free
Gβγ subunits mediate activation of the MAP kinase
signaling pathway in the same way as Gi-coupled
receptors. Increase of intracellular cAMP levels
leads diverse cell functions as cell proliferation,
differentiation, angiogenesis and migration (Daaka
et al., 1997).
Implicated in
Ovarian carcinoma
Prostate cancer
Note
Reverse transcriptase-PCR studies indicated
constitutive expression of β2 adrenergic receptor on
ovarian carcinoma cell lines (Lutgendorf et al.,
2003). Lutgendorf et al. (Lutgendorf et al., 2003)
investigated the effects of norepinephrine and
isoproterenol (a nonspecific-adrenergic agonist) on
the production of vascular endothelial growth factor
(VEGF) by ovarian cancer cell lines; and found that
both,
norepinephrine
and
isoproterenol,
significantly enhanced VEGF production. These
effects were blocked by thenon-specific β
antagonist propranolol, supporting a role
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Note
β2 adrenergic receptor signaling was related to
prostate cancer cell progression (Sastry et al., 2007;
Zhang et al., 2011). β2 adrenergic receptor
activation of PKA signaling pathway has been
associated with reduction of sensitivity of prostate
cancer cells to apoptosis (Sastry et al., 2007) and
promotion of cell proliferation and cell migration
(Zhang at al., 2011).
Contrastingly, other investigation demonstrated that
the genetic silencing of β2 adrenergic receptor
increases cell migration and invasion of normal
660
ADRB2 (adrenoceptor beta 2, surface)
Oliveira DT, Bravo-Calderón DM
prostate cells and that the weak expression of this
protein is associated with metastases and with worst
survival rates in prostate cancer patients (Yu et al.,
2007).
carcinoma cells lines (Yang et al., 2006); as well
upregulated the production of VEGF, interleukin
(IL)-8, and IL-6 in human melanoma tumor cell
lines (Yang et al., 2009).
Esophageal squamous cell
carcinoma
References
Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the
coupling of the beta2-adrenergic receptor to different G
proteins by protein kinase A. Nature. 1997 Nov
6;390(6655):88-91
Note
Liu et al. (Liu et al., 2008b) demonstrated that
stimulation of β2 adrenergic receptor with
epinephrine significantly increase the esophageal
cancer cell proliferation accompanied by elevation
of the expression of VEGF, VEGF receptor
VEGFR-1 and VEGFR-2. In addition, it has been
shown that the epidermal growth factor mediates
the mitogenic signals in esophageal cancer cells
through transactivation of β2 adrenergic receptor
(Liu et al., 2008a).
Kohm AP, Sanders VM. Norepinephrine and beta 2adrenergic receptor stimulation regulate CD4+ T and B
lymphocyte function in vitro and in vivo. Pharmacol Rev.
2001 Dec;53(4):487-525
Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J,
Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK.
Stress-related mediators stimulate vascular endothelial
growth factor secretion by two ovarian cancer cell lines.
Clin Cancer Res. 2003 Oct 1;9(12):4514-21
Oral squamous cell carcinoma
(OSCC)
McGraw DW, Liggett SB. Molecular mechanisms of beta2adrenergic receptor function and regulation. Proc Am
Thorac Soc. 2005;2(4):292-6; discussion 311-2
Note
Genetic and protein expression of β2 adrenergic
receptor was demonstrated in OSCC by using RTPCR
assay,
Western
blot
and
immunohistochemistry (Shang et al., 2009; Bernabé
et al., 2011; Bravo-Calderón et al., 2011-2012).
Investigations performed in different oral cancer
cell lines demonstrated that β2 adrenergic receptor
signaling by norepinephrine increases cell
proliferation and invasion, and upregulates
interleukin-6 (IL-6) gene expression and protein
release (Shang et al., 2009; Bernabé et al., 2011).
Furthermore, Shang et al. (Shang et al., 2009)
reported
that
malignant
cell
positive
immunoexpression of β2-AR was significantly
correlated with age, tumor size, clinical stage and
cervical lymph node metastasis in OSCC patients,
and that β2-AR may play an important role in the
formation and metastasis of oral cancer. However, a
retrospective clinical study of a large number of
patients showed that patients with OSCC who
exhibited strong β2-AR immunohistochemical
expression
by
malignant
epithelial
cells
demonstrated higher survival rates compared to
patients with weak/negative β2-AR expression
(Bravo-Calderón et al., 2011-2012). Therefore,
further clinical and laboratory studies are warranted
to elucidate the role of β2 adrenergic receptor
activation in oral squamous cell carcinoma.
Johnson M. Molecular mechanisms of beta(2)-adrenergic
receptor function, response, and regulation. J Allergy Clin
Immunol. 2006 Jan;117(1):18-24; quiz 25
Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker
PH, Li Y, Gershenson DM, Lutgendorf S, Cole SW. Stress
hormone-mediated invasion of ovarian cancer cells. Clin
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Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R,
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M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL,
Landen CN, Li Y, Felix E, Sanguino AM, Newman RA,
Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G,
Lutgendorf SK, Cole SW, Sood AK. Chronic stress
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Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB,
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Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B,
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11;282(19):14094-100
Yu J, Cao Q, Mehra R, Laxman B, Yu J, Tomlins SA,
Creighton CJ, Dhanasekaran SM, Shen R, Chen G, Morris
DS, Marquez VE, Shah RB, Ghosh D, Varambally S,
Chinnaiyan AM. Integrative genomics analysis reveals
silencing of beta-adrenergic signaling by polycomb in
prostate cancer. Cancer Cell. 2007 Nov;12(5):419-31
Various cancers
Note
β2
adrenergic
receptor
was
also
immunohistochemically
identified
in
nasopharyngeal carcinoma (Yang et al., 2006) and
in melanoma (Yang et al., 2009). Norepinephrine
treatment increased MMP-2, MMP-9, and VEGF
levels in culture supernatants of nasopharyngeal
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Liu X, Wu WK, Yu L, Li ZJ, Sung JJ, Zhang ST, Cho CH.
Epidermal growth factor-induced esophageal cancer cell
proliferation
requires
transactivation
of
betaadrenoceptors. J Pharmacol Exp Ther. 2008a
Jul;326(1):69-75
Liu X, Wu WK, Yu L, Sung JJ, Srivastava G, Zhang ST,
Cho CH. Epinephrine stimulates esophageal squamous-
661
ADRB2 (adrenoceptor beta 2, surface)
Oliveira DT, Bravo-Calderón DM
cell carcinoma cell proliferation via beta-adrenoceptordependent transactivation of extracellular signal-regulated
kinase/cyclooxygenase-2 pathway. J Cell Biochem. 2008b
Sep 1;105(1):53-60
carcinoma cells. Brain Behav Immun. 2011 Mar;25(3):57483
Bravo-Calderón DM, Oliveira DT, Marana AN, Nonogaki S,
Carvalho AL, Kowalski LP. Prognostic significance of beta2 adrenergic receptor in oral squamous cell carcinoma.
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Rosenbaum DM, Rasmussen SG, Kobilka BK. The
structure and function of G-protein-coupled receptors.
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Steenhuis P, Huntley RE, Gurenko Z, Yin L, Dale BA,
Fazel N, Isseroff RR. Adrenergic signaling in human oral
keratinocytes and wound repair. J Dent Res. 2011
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Shang ZJ, Liu K, Liang de F. Expression of beta2adrenergic receptor in oral squamous cell carcinoma. J
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Zhang P, He X, Tan J, Zhou X, Zou L. β-arrestin2
mediates β-2 adrenergic receptor signaling inducing
prostate cancer cell progression. Oncol Rep. 2011
Dec;26(6):1471-7
Sivamani RK, Pullar CE, Manabat-Hidalgo CG, Rocke DM,
Carlsen RC, Greenhalgh DG, Isseroff RR. Stress-mediated
increases in systemic and local epinephrine impair skin
wound healing: potential new indication for beta blockers.
PLoS Med. 2009 Jan 13;6(1):e12
Loenneke JP, Wilson JM, Thiebaud RS, Abe T, Lowery
RP, Bemben MG. β2 Adrenoceptor signaling-induced
muscle hypertrophy from blood flow restriction: is there
evidence? Horm Metab Res. 2012 Jun;44(7):489-93
Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC,
Webster Marketon JI, Barsky SH, Glaser R.
Norepinephrine upregulates VEGF, IL-8, and IL-6
expression in human melanoma tumor cell lines:
implications for stress-related enhancement of tumor
progression. Brain Behav Immun. 2009 Feb;23(2):267-75
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Oliveira DT, Bravo-Calderón DM. ADRB2 (adrenoceptor
beta 2, surface). Atlas Genet Cytogenet Oncol Haematol.
2014; 18(9):659-662.
Bernabé DG, Tamae AC, Biasoli ÉR, Oliveira SH. Stress
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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
662
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
IRF4 (interferon regulatory factor 4)
Vipul Shukla, Runqing Lu
Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha,
NE 68118, USA (VS, RL)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/IRF4ID231ch6p25.html
DOI: 10.4267/2042/54034
This article is an update of :
Rasi S, Gaidano G. IRF4 (interferon regulatory factor 4). Atlas Genet Cytogenet Oncol Haematol 2009;13(12):941-943.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
mRNA is expressed at high levels in lymphoid
tissues, in skin and in tonsils.
Review on IRF4, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
Protein
Identity
Description
Protein length: 451 amino acids.
Calculated molecular weight of 51,8 kDa.
Other names: IRF-4, LSIRF, MUM1, NF-EM5
HGNC (Hugo): IRF4
Location: 6p25.3
Local order: IRF4 is located on chromosome 6 at
the telomeric extremity of the short arm, and lies
between the DUSP22 (dual specificity phosphatase
22) and EXOC2 (exocyst complex component 2)
genes.
Note
IRF4 belongs to the IRF (interferon regulatory
factors) family of transcription factors and is a
critical transcriptional regulator of immune system
development and function.
Expression
IRF4 protein is expressed predominantly in blood
cells. However, its expression can also be detected
in adipocytes and melanocytes.
In blood cells, expression of IRF4 can be detected
in T, B, DC and macrophages. Expression of IRF4
in T and B cells is strongly induced by antigen
receptor signaling.
Localisation
Nucleus.
Function
In the immune system, IRF4 is critical for
development and maturation of multiple lineages of
blood cells. In T cells development, IRF4 is
essential for the differentiation of Th1, Th2, Th9,
Th17 and T reg subsets. In B lymphocytes, IRF4
promotes
light
chain
rearrangement
and
transcription and is critical for B cell development
at the pre-B stage.
IRF4 antagonizes Notch signaling and limits the
size of marginal zone B cells (Simonetti et al.,
2013).
DNA/RNA
Description
Gene of 19,4 kb with 9 exons and 8 introns.
Exon 1, the 5' part of exon 2 and the 3' part of exon
9 are non coding.
Transcription
Length of the transcript is 5314 bp.
Coding sequence: CDS 114-1469.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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IRF4 (interferon regulatory factor 4)
Shukla V, Lu R
In addition, IRF4 is essential for class-switching
and plasma cell differentiation. In B cells, IRF4
interacts with Ets family of trancription factor
(PU.1/spi-B) through EICE site whereas in T cells,
IRF4 interacts with AP-1 family of trancription
factor (BATF) through AICE site. Also, IRF4 is
required for the differentiation of dendritic cells
(DCs), particularly the CD11b(+) subset (Schlitzer
et al., 2013). In macrophages, IRF4 promotes the
differentiation and polarisation to the M2 subtype
also known as the tumor associated macrophages.
Recent studies have identified a role of IRF4 in
adipocyte biology. IRF4 has been shown to regulate
enzymes required for lipolysis in adipocytes.
Therefore, an adipocyte specific deletion of IRF4
causes enhanced lipid synthesis, dysregulated lipid
homeostasis eventually leading to obesity.
Interestingly, in melanocytes IRF4 was recently
identified to cooperate with another transcription
factor, MITF to positively regulate the expression
of tyrosinase gene required for melanin synthesis.
Additionally, the SNPs in the IRF4 gene locus have
been identified as risk alleles for developing
melanoma.
course. IRF4 is obligatory required for the terminal
differetiation of mature B cells to plasma cells and
has been shown to play a central role in the
pathogenesis of MM. IRF4 is recurrently
translocated and juxtaposed to the IgH promoter
t(6;14)(p25;q32) in a significant proportion (~21%)
of MM cases. More commonly, IRF4 have been
shown to be overexpressed without genetic
alterations in majority of MM cases and MM cells
are particularly sensitive to the down-regulation of
IRF4.
Cytogenetics
t(6;14)(p25;q32) --> IRF4 - IgH.
Hybrid/Mutated gene
The translocation juxtaposes the IgH locus to the
IRF4 gene.
Oncogenesis
The precise mechanism for pathogenesis of MM in
presence of high levels of IRF4 is mediated by an
autoregulatory loop established between IRF4 and
c-myc in MM cells. Recently, IRF4 has been shown
to regulate caspase-10 leading to disruption of
normal autophagy mechanisms in MM cells
thereby, causing prolonged survival of these cells.
Homology
Chronic lymphocytic leukemia (CLL)
Among IRF family members, IRF4 is highly
homologous to IRF8.
Disease
CLL is the most common adult leukemia in the
western countries. It is a heterogeneous B-cell
malignancy marked by progressive accumulation of
CD5 positive mature B lymphocytes. A Genome
Wide Association Study (GWAS) recently
identified SNPs in the 3' UTR of IRF4 gene locus in
patients with CLL. The individuals carrying the risk
alleles harboring the SNPs have lower levels of
IRF4 and poorer outcomes compared to individuals
carrying the non-risk allele. Another study
identified mutations in the DNA binding domain of
IRF4 in a small subset (1,5%) of CLL cases. More
recently, using two distinct murine genetic models,
it has been shown that low levels of IRF4 are
causally related to the development of CLL.
Prognosis
CLL patients with low levels of IRF4 have
aggressive disease course and poor prognosis.
Mutations
Germinal
SNPs in the IRF4 gene locus have been identified
in patients with chronic lymphocytic leukemia and
melanoma.
Somatic
Somatic mutations in DNA binding domain of IRF4
have been identified in a small subset (1,5%) of
chronic lymphocytic leukemia (CLL) patients.
Implicated in
Multiple myeloma (MM)
Disease
Multiple myeloma (MM) is a plasma cell derived
malignancy with a particularly aggressive clinical
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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IRF4 (interferon regulatory factor 4)
Shukla V, Lu R
Hodgkins lymphoma (HL)
Cytogenetics
Although reciprocal translocations are extremely
rare in CLL, a translocation disrupting IRF4 gene
locus t(1;6)(p35.3;p25.2) was identified in a small
subset of CLL patients with aggressive disease.
Hybrid/Mutated gene
Mutations in the DNA binding domain of IRF4
with a yet undefined function in B cells were
identified in a small subset of CLL cases.
Oncogenesis
The precise mechanism for oncogenesis of CLL in
presence of low levels of IRF4 is not yet known.
Disease
Hodgkins lymphoma (HL) is an enigmatic B cell
malignancy that is characterized by lack of
expression of several B cell markers.
The Hodgkin and Reed Sternberg (HRS) cells
present in HL cases are presumably derived from
germinal center B cells. IRF4 is overexpressed in
majority of classical HL cases and is shown to
mediate the survival of these cells. Paradoxically,
the SNPs in IRF4 linked to its lower expression
levels and associated with the development of CLL
are also shown to be linked to the risk of
developing HL.
Oncogenesis
Whether the overexpression of IRF4 in HRS cells
of HL is causal is unclear. However, some studies
have linked the survival and proliferation of HRS
cells to the expression of IRF4.
Diffused large B cell lymphoma
(DLBCL)
Disease
Diffuse large B cell lymphoma represents a
heterogeneous
malignancy
that
arises
spontaneously or develop from pre-existing
leukemia. On the basis of gene expression profiling
DLBCL is divided into three distinct subtypes
namely the germinal center subtype (GCB), the
activated B cell subtype (ABC) and the mediastinal
subtype. The three subtypes presumably arise from
three distinct B cell subtypes. IRF4 is primarily
overexpressed in the ABC type of DLBCL while
GCB subtype is marked by lower expression of
IRF4.
Prognosis
IRF4 is overexpressed in the ABC type DLBCL
which is most aggressive form of DLBCL and have
poorer patient outcomes compared to other
subtypes.
Cytogenetics
IRF4 is overexpressed in a small group of patients
with a reciprocal translocation between IgG locus
and the IRF4 t(1;6)(p35.3;p25.2). The patients
carrying the translocation primarily belong to GCB
or follicular lymphoma grade 3 type is associated
with favorable patient outcomes.
Oncogenesis
IRF4 induces the expression of transcription factor
Blimp-1 and directly suppresses the expression of
Bcl-6 to allow terminal differentiation of activated
B cells to plasma cells. However, this molecular
network is short circuited in ABC DLBCL by
recurrent mutational inactivation of Blimp-1.
Additionally, mutations located in the promoter
region of Bcl-6 that disrupt the IRF4 binding sites
and leads to enhanced expression of Bcl-6 were
identified in a small group of patients. These
genetic events disrupt the molecular network
required for plasma cell differentiation. However,
the precise functional role of IRF4 in pathogenesis
of ABC type DLBCL is not well defined.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Primary cutaneous anaplastic large
cell lymphoma (C-ALCL)
Disease
Primary cutaneous anaplastic large cell lymphoma
(C-ALCL) is a T cell lymphoma with an indolent
disease course and presence of tumor lesions in the
skin. The lesions in C-ALCL almost never spread
extra-cutaneously and often regress spontaneously.
IRF4 is overexpressed in C-ALCL but not in the
more aggressive form of the disease known as
peripheral T cell lymphoma not otherwise specified
(PTCL-NOS). The overexpression of IRF4 in some
cases is associated with a recurrent translocations a
subset of them placing the IRF4 gene next to the T
cell
receptor
alpha
(TCRA)
promoter
t(6;14)(p25;q11.2). Other translocations identified
do not involve TCRA.
Cytogenetics
IRF4 is translocated primarily in the C-ALCL
however the precise breakpoints are not defined. In
a small subset of the cases with translocations IRF4
is
juxtaposed
to
the
TCRA
locus
t(6;14)(p25;q11.2).
B cell acute lymphoblastic leukemia
(B-ALL)
Disease
B cell acute lymphoblastic leukemia (B-ALL) is a
B cell malignancy derived from early B cells. IRF4
is shown to play a tumor suppressive role in BALL. IRF4 is shown to suppress the oncogenesis of
both BCR-ABL and c-myc induced B-ALL.
Oncogenesis
IRF4 inhibits B-ALL by regulating the expression
of negative regulators of cell cycle p27.
665
IRF4 (interferon regulatory factor 4)
Shukla V, Lu R
the screen map to a putative enhancer region in the
IRF4 gene locus.
Oncogenesis
Recently, the SNP identified in IRF4 locus were
demonstrated to decrease IRF4 expression by
disruption of specific transcription factor binding
sites. Additionally, IRF4 corroborates with
micropthalmia associated transcription factor
(MITF) to regulate the expression of enzyme
tyrosinase responsible for melanin production.
These studies point towards a critical role for IRF4
in melanocyte biology and also its association with
skin cancer.
Chronic myeloid leukemia (CML)
Disease
Chronic myeloid leukemia (CML) is a
myeloproliferative disorder marked by clonal
expansion of granulocytes. It is associated with a
hallmark translocation and presence of a fusion
BCR-ABL protein in majority of patients. IRF4 is
shown to be underexpressed in CML patients along
with its highly homologous family member IRF8.
However the functional role of IRF4 in CML is not
well characterized.
Virus implicated malignancies
Disease
Viruses like Epstein Barr virus (EBV), human T
cell leukemia virus-1 (HTLV1) and Kaposi
Sarcoma associated herpes virus (KSHV/HHV-8)
are implicated in B cell malignancies, adult T cell
leukemia (ATL) and primary effusion lymphoma
(PEL) respectively. The proteins encoded by these
viruses, directly or indirectly activate NF-kB
signaling which in turn activates the expression of
IRF4. As a result IRF4 is overexpressed in these
virus implicated malignancies. The knockdown of
IRF4 in EBV transformed B cells lead to downregulation of genes involved in cellular
proliferation. The role of IRF4 in HTLV-1 induced
ATL is not clear however few reports indicate its
involvement in regulation of cell cycle associated
genes. The role of IRF4 in KSHV induced kaposi's
sarcoma and PEL is ambiguous. KSHV encodes
viral homologs of cellular IRFs called vIRFs. The
vIRF4 is shown to inhibit the function of cellular
IRF4 leading to induction of lytic cycle for KSHV
replication.
Oncogenesis
The role of IRF4 in these viral implicated
malignancies is still unclear. However, the
activation status of NF-kB by these viruses
invariably co-relates with IRF4 expression in these
cells.
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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
This article should be referenced as such:
Shukla V, Lu R. IRF4 (interferon regulatory factor 4). Atlas
Genet Cytogenet Oncol Haematol. 2014; 18(9):663-667.
667
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
PLCG1 (Phospholipase C, Gamma 1)
Rebeca Manso
Pathology Department, Fundacion Conchita Rabago, IIS "Fundacion Jimenez Diaz", E-28040 Madrid,
Spain (RM)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/PLCG1ID44163ch20q12.html
DOI: 10.4267/2042/54035
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Abstract
PLCG1 is expressed ubiquitously, especially in the
brain, thymus, intestine and lungs. Additionally,
PLCG1 is overexpressed in numerous cancer types
such as human colorectal cancer (Noh et al., 1994),
breast carcinoma (Arteaga et al., 1991), prostate
carcinoma (Peak et al., 2008), familial adenomatous
polyposis (Park et al., 1994) and human skins under
hypeproliferative conditions (Nanney et al., 1992).
Review on PLCG1, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
Identity
Other names: NCKAP3, PLC-II, PLC1, PLC148,
PLCgamma1
HGNC (Hugo): PLCG1
Location: 20q12
Local order: From the cytosol.
Localisation
PLCG1 localizes predominantly in the plasmatic
membrane, cytoplasm and nucleus.
DNA/RNA
Function
Description
PLCG1 is a protein involved in multiple cellular
processes. A potent inhibitor of PLCG1 (U-73122)
has been reported to inhibit PLCG1-dependent
processes in cells (Smith et al., 1990; Thompson et
al., 1991; Thomas et al., 2003; Li et al., 2005).
The inhibition of PLCG1 may be an important
mechanism for an antiproliferative effect on the
human cancer cells.
Role in the production of the second messenger
molecules: PLCG1 mediates the production of
diacylglycerol (DAG) and inositol 1,4,5trisphosphate (IP3) from the hydrolysis of
phosphatidynositol-4,5-bisphosphate
(PIP2)
(Williams et al., 1996). These second messengers
are essential for T cell activation (Lin et al., 2001).
The PLCG1 gene spans 38.762 kb on the genomic
DNA. The gene includes 32 exons.
Transcription
There are two transcript variants: 5205 bp (isoform
a) and 5202 bp (isoform b).
Protein
Description
The PLCG1 protein encodes two alternative
isoforms: variant a (P19174-1)-1290 amino acids,
148.53 Da; variant b (P19174-2)-1291 amino acids,
148.66 Da.
Figure 1. Schematic diagram of PLCG1 location on chromosome 20. PLCG1 localizes to chromosome 20q12, which is
represented graphically. PLCG1 gene spans 38.762 kb on the genomic DNA.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
668
PLCG1 (Phospholipase C, Gamma 1)
Manso R
Figure 2. Schematic representation of the domains of PLCG1. The protein contains eight domains, four of which are unique
to PLCG family. The PLCG 'specific array' of domains, comprising a "split" PH domain flanking two tandem SH2 domains and
one SH3 domain, is inserted between the two halves (X and Y) of the TIM-barrel catalytic domain. Several other domains
including two PH domains, one C2 domain and one EF hand motifs. The numering of the amino acid residues is for human
PLCG1 (Suh et al., 2008; Bunney and Katan, 2011).
Role in cellular proliferation: PLCG1 is associated
with tumor development, and it is overexpressed in
some tumors (Shin et al., 2007). This
overexpression stimulates MMP-3 expression.
PLCG1 is required for metastasis development
(Sala et al., 2008).
Role in angiogenesis: PLCG1 plays an important
role in angiogenesis (Husain et al., 2010). PLCG1
is activated by vascular endothelial growth factor
receptor-2 (VEGFR-2) in endothelial cells (Singh et
al., 2007) and in neoplastic Barrett's cells (Zhang et
al., 2013).
Role in the regulation of intracellular signaling:
PLCG1 plays a role in mediating T-cell activities
downstream of TCR activity.
PLCG1 can be activated by receptor tyrosine
kinases: EGFR (Nishibe et al., 1990; Wu et al.,
2009), PDGFR (Larose et al., 1993), FGFR (Peters
et al., 1992), NGFR (Middlemas et al., 1994) and
HGFR (Davies et al., 2008). PLCG1 is a molecule
associate with lipid rafts, it translocates from the
cytosol to lipid rafts during TCR signaling (Verí et
al., 2001).
Role in the mobilization of Ca2+: this process is to
activate phosphatase calcineurin, which in turn
dephosphorylates and activates NFAT (Rao et al.,
1997).
Truncation of the N terminus of Vav1 is
accompanied by a decrease in PLCG1
phosphorylation and this inhibits calcium
mobilization (Knyazhitsky et al., 2012).
Role in cytoskeleton: PLCG1 plays a role in actin
reorganization (Pei et al., 1996; Wells, 2000; Wang
et al., 2007; Li et al., 2009).
Role in adhesion and migration: PLCG1 mediates
cell adhesion and migration through an undefined
mechanism (Wang et al., 2007; Crooke et al.,
2009). PLCG1 plays a role in integrin-mediated cell
motility processes (Jones et al., 2005).
Role in apoptosis: PLCG1 is proteolytically cleaved
by group II caspases especially by caspase-3 and
caspase-7 during apoptosis. This results in the loss
of receptor-mediated tyrosine phosphorylation (Bae
et al., 2000). PLCG1 plays a protective role in
H2O2-induced PC12 cells death (Yuan et al., 2009).
The Fas-mediated apoptosis requires endoplasmic
reticulum-mediated calcium release in a mechanism
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
dependent on PLCG1 activation (Wozniak et al.,
2006).
Role in transformation: PLCG1 interacts with
Middle tumor antigen (MT).
The tyrosine phosphorylation level of PLCG1 is
elevated in cells expressing wild type MT but not in
cells expressing Tyr322→Phe MT (Su et al., 1995).
Role in autoimmune symptoms: PLCG1 deficiency
impairs the development and function regulatory
cells (FoxP3+), causing inflammatory/autoimmune
symptoms (Fu et al., 2010).
Homology
The protein contains eight domains, four of which
are unique to PLCG family (Suh et al., 2008).
The PLCG 'specific array' of domains, comprising a
"split" PH domain flanking two tandem SH2
domains and one SH3 domain, is inserted between
the two halves (X and Y) of the TIM-barrel
catalytic domain (Bunney and Katan, 2011).
Several other domains including two PH domains,
one C2 domain and one EF hand motifs (Suh et al.,
2008).
Mutations
Somatic
99 mutations have been described in the PLCG1
gene, according to the Catalogue of Somatic
Mutations in Cancer (COSMIC) database.
De novo mutation has been described in patients
with Cutaneous T-cell lymphoma (CTCL): S345F
(10/53 analyzed CTCL samples, 19%) (Vaqué et
al., 2014).
Implicated in
Breast cancer
Oncogenesis
Overexpression of PLCG1 is a marker of
development of metastases in breast cancer
(Lattanzio et al., 2013).
Loss of PLCG1 in part mimicked the effect of miR200b/miR-c/miR-429 overexpression in viability,
apoptosis and EGF-driven cell invasion of breast
cancer cells (Uhlmann et al., 2010).
669
PLCG1 (Phospholipase C, Gamma 1)
Manso R
signaling towards NFAT activation (Vaqué et al.,
2014).
Colorectal cancer
Oncogenesis
PLCG1 has a potencial role in colon cancer
(Nomoto et al., 1995; Li et al., 2005; Reid et al.,
2009). The activity of PLCG1 is reduced in STAT3
Y705F mutant colorectal cancer cells (Zhang et al.,
2011), it shows that there is crosstalk between
STAT3 and PLCG1 signaling pathways.
Brain disorders
Note
Jang et al., 2013.
Oncogenesis
PLCG1 is highly expressed in brain. Abnormal
expression and activation of PLCG1 appears in
epilepsy (He et al., 2010), bipolar disorder (Løvlie
et al., 2001), depression (Dwivedi et al., 2005),
Huntington's disease (Giralt et al., 2009) and
Alzheimer's disease (Shimohama et al., 1995).
Prostate carcinoma
Oncogenesis
PLCG1 has a role in the regulation of PC3LN3
(human prostate carcinoma cells) cell adhesion that
appears to be independent of its effects on tumour
cell chemotactic migration and spreading in
response to extracellular matrix (Peak et al., 2008).
Myocardial dysfunction in sepsis
Oncogenesis
PLCG1 signaling induces cardiac TNF-alpha
expression and myocardial dysfunction during
Lipopolysaccharide (LPS) stimulation. Inhibition of
PLCG1 decreased cardiac TNF-alpha expression
and LPS-induced myocardial dysfunction was also
attenuated (Peng et al., 2008).
Gastric cancer
Oncogenesis
PLCG1 plays a role in RhoGDI2-mediated cisplatin
resistance and cell invasion in gastric cancer (Cho
et al., 2011).
Squamous cell carcinoma (SCC)
To be noted
Oncogenesis
PLCG1 is a downstream target of EGFR signaling.
PLCG1 is required for EGFR-induced SCC cell
mitogenesis (Xie et al., 2010).
Note
miR that target PLCG1: PLCG1 is target of
different
microRNAs,
according
to
the
bioinformatic
algorithms
microRNA
(microRNA.org).
Oral potentially malignant lesions
(OPLs)
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This article should be referenced as such:
Bunney TD, Katan M. PLC regulation: emerging pictures
for molecular mechanisms. Trends Biochem Sci. 2011
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Manso R. PLCG1 (Phospholipase C, Gamma 1). Atlas
Genet Cytogenet Oncol Haematol. 2014; 18(9):668-672.
672
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
SLC1A5 (solute carrier family 1 (neutral amino
acid transporter), member 5)
Cesare Indiveri, Lorena Pochini, Michele Galluccio, Mariafrancesca Scalise
Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular
Biotechnology, University of Calabria, 87036 Arcavacata di Rende, Italy (CI, LP, MG, MS)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC1A5ID42313ch19q13.html
DOI: 10.4267/2042/54036
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
constituted by 1737 nucleotides and differs in the 5'
UTR from the variant NM_005628.
In NM_001145144 the translation starts
downstream the third exon generating a shorter
peptide of 313 aa.
The third isoform NM_ 001145145 has 1927
nucleotides and lacks the first exon. It presents a
different translation start at 5', coding a peptide of
339 amino acids. A longer transcript,
XM_005259167, is reported only in NCBI
database.
It has been identified by automated computational
analysis. More than 400 SNP(s), both in coding and
non-coding regions of the SLC1A5 gene, are
reported in dbSNP database (dbSNP). More than 40
are responsible of amino acid substitutions with
unknown significance. Only the variant SLC1A5P17A (rs3027956) is associated with breast cancer
(Savas et al., 2006). A region constituted by 907 bp
upstream of the ASCT2 gene possesses promoter
activity (Bungard and McGivan, 2004). In this
region the following putative elements have been
identified: an amino acid-regulatory element, a
consensus site for binding of the transcription factor
activator protein 1 (AP1) and a consensus binding
sites for nuclear and hepatocyte nuclear factors.
Abstract
Review on human SLC1A5, with data on
DNA/RNA, on the protein encoded and
pathological and physiological implications.
Identity
Other names: AAAT, ASCT2, ATBO, M7V1,
M7VS1, R16, RDRC
HGNC (Hugo): SLC1A5
Location: 19q13.32
Local order: Orientation: minus strand.
DNA/RNA
Description
The SLC1A5 gene, located at 19q13.3, counts
28692 nucleotides with 8 exons. It has been found
in 56 different organisms (NCBI). The gene
encodes a protein involved in sodium-dependent
neutral amino acid transport (Kekuda et al., 1996;
Pingitore et al., 2013).
Transcription
Three isoforms (transcripts) are reported either on
NCBI and Ensembl databases for SLC1A5 human
gene, deriving from different translation start. They
differ in length, particularly at 5' extremity. The
first variant NM_005628 represents the longest
transcript, constituted by 2873 nucleotides and 8
exons. This transcript encodes a peptide of 541
amino acids. The second variant NM_001145144 is
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Pseudogene
The gene is virtually present in all vertebrates. The
better known orthologous of the human gene are
those from rat, mouse and rabbit. Identity between
the human and rat, mouse, rabbit are 79%, 82% and
85%, respectively.
673
SLC1A5 (solute carrier family 1 (neutral amino acid transporter), member 5)
Indiveri C, et al.
Figure 1. Isoforms of SLC1A5 gene. The three isoforms are present in the minus strand of the chromosome 19 in position
19q13.3. NM_005628: isoform one, encodes for the longest peptide and is constituted by 8 exons; NM_001145144: isoform two,
due to alternative splicing is characterized by only four exons; NM_ 001145145: isoform three presents seven exons. The
nucleotide sequence is depicted as black lines. Coding nucleotides and untranslated (UTR) regions are indicated by red and
white boxes, respectively. Exons are indicated by roman numbers.
Protein
Function
Description
Transport mediated by the human ASCT2 has been
originally studied in intact cell systems overexpressing the transport protein (Kekuda et al.,
1996; Kekuda et al., 1997).
Recently, hASCT2 was over-expressed in the yeast
P. pastoris, purified and reconstituted in artificial
phospholipid vesicles (proteoliposomes), in absence
of other interfering transporters.
All experimental systems concur in demonstrating
that hASCT2 is an obligate exchanger of neutral
amino acid.
This antiport requires the presence of extracellular
Na+ which cannot be substituted by Li+ or K+. The
Na+ ex:amino acidex stoichiometry of the human
transporter is likely to be 1:1. Competition studies
on 3H-glutamine, 3H-threonine or 3H-alanine
transport performed in cells indicated that other
potential substrates of hASCT2 are valine, leucine,
serine, cysteine, asparagine, methionine, isoleucine,
tryptophan, histidine, phenylalanine. While
glutamate, lysine, arginine along with MeAIB [α(methylamino)isobutyric acid] and BCH [2aminobicyclo-(2,2,1)-heptane-2-carboxylic
acid]
are neither transported nor inhibit hASCT2.
Experiments
with
radioactive
compounds
confirmed the competition data (Torres-Zamorano
et al., 1998). In proteoliposomes, inhibition has
been confirmed for most but not for all of the amino
acids.
Moreover,
proteoliposome
studies
highlighted an asymmetric specificity for amino
acids allowing to distinguish the amino acids
inwardly transported (alanine, cysteine, valine,
methionine) from those bi-directionally transported
(glutamine, serine, asparagine, and threonine).
541 amino acids; molecular mass 56598,34 Da.
Human SLC1A5 is a permease (membrane
transporter).
The 3D structure is not available. Homology
modeling highlights a structure similar to that of the
glutamate transporter of P. horikoshii (1XFH). Nand C-terminal ends are intracellular. Potential site
of N-glycosylation and phosphorilation are
predicted.
In the structural model, at least one glycosylation
site is extracellular and the phosphorilation sites are
intracellular (Fig. 2).
Expression
Human SLC1A5 has been originally named ASCT2
from AlaSerCysTransporter2 or ATB0.
The acronym ASCT2 is the most frequently used to
designate this transport system.
It is expressed in many tissues, including brain,
(Bröer and Brookes, 2001; Deitmer et al., 2003;
Gliddon et al., 2009).
There is functional evidence of the expression of
ASCT2 in kidney and intestine (Bode, 2001).
Besides Caco-2 cells, apparently, also the HT-29
intestinal cell line functionally expresses ASCT2
(Kekuda et al., 1996; Kekuda et al., 1997).
Poly(A)1 RNA isolated from several tissues of
human origin revealed expression in placenta, lung,
skeletal muscle, kidney, and pancreas (Kekuda et
al., 1996).
Localisation
The protein is localized in the plasma membrane.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
674
SLC1A5 (solute carrier family 1 (neutral amino acid transporter), member 5)
Indiveri C, et al.
Figure 2. Homology structural model of hASCT2. Ribbon diagram viewing of the transporter from the lateral side. The model
was built using the glutamate transporter Glpth from Pyrococcus horikoshii crystal structure (1XFH) as the template by Modeller
V9.13. The homology model was represented using SpdbViewer 4.01. Asn 163 and 212, predicted as glycosilation sites, are
highlighted in blue; Ser 183, 261 and Thr 206, 207, 329, predicted as phosphorilation sites are highlighted in red and orange,
respectively. Prediction according to Scan Prosite.
The functional asymmetry was also confirmed by
the kinetic analysis of [3H]glutamine/glutamine
antiport: different Km values were measured on the
external and internal sides of proteoliposomes,
0,097 and 1,8 mM, respectively.
The SH reagents HgCl2, mersalyl and pOHMB
potently inhibited hASCT2 mediated transport
(Pingitore et al., 2013).
The physiological role of hASCT2 consists in
providing cells with some neutral amino acids
exporting others on the basis of the metabolic need
of cells consistently with the intra and extracellular
amino acid concentrations. In brain, particularly,
hASCT2 contributes to glutamine homeostasis of
neurons and astrocytes. On the basis of experiments
performed with animal models, it was hypothesized
that hASCT2 mediates efflux of glutamine from
astrocytes, a process that is critical for the
functioning of the glutamate-glutamine cycle to
recover synaptically released glutamate in exchange
with glutamine efflux (Bröer et al., 1999). The
glutamine-glutamate cycle has been shown also in
placenta. Glutamine crosses the placenta and enters
the fetal liver where it is deamidated to glutamate.
About 90% of glutamate generated by the liver is
taken up by the placenta and used in the
metabolism. The glutamine-glutamate cycle
between the placenta and the fetal liver is
obligatory for the generation of NADPH in the
placenta (Torres-Zamorano et al., 1998). Among
other functions reported for hASCT2 there is the
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
regulation of mTOR pathway, translation and
autophagy. The transporter regulates an increase in
the intracellular concentration of glutamine which
is then used by another plasma membrane
transporter, named LAT1 (SLC7A5) (Galluccio et
al., 2013) as efflux substrate to regulate the uptake
of extracellular leucine with subsequent activation
of mTORC1 (Nicklin et al., 2009). Moreover, it has
been proposed that a group of retroviruses
specifically uses the hASCT2 as a common cell
surface receptor following a co-evolution
phenomenon. The orthologous murine transporter
mASCT2 is inactive as a viral receptor (Marin et
al., 2003).
Implicated in
Molecular basis of cancerogenesis
Note
Tumor cells acquire altered metabolism. Due to
these changes, the expression of membrane
transporters involved in providing nutrients is
altered. The plasma membrane transporter for
glutamine ASCT2 has been clearly associated to
cancer development and progression, together with
another amino acid membrane transporter, LAT1
specific for glutamine and other neutral amino acids
(Fuchs and Bode, 2005). The energetic needs of
cancer cells are different from normal ones due to
the Warburg effect. According to this phenomenon
ATP derives from anaerobic glycolisis bypassing
675
SLC1A5 (solute carrier family 1 (neutral amino acid transporter), member 5)
mitochondrial function (Ganapathy et al., 2009). In
this scenario glutamine provided by means of
ASCT2 and LAT1 transport function sustains tumor
growth and signaling through mTOR pathway
(Nicklin et al., 2009).
The importance of ASCT2 in this network is
revealed by induction of apoptosis when silencing
its gene in human hepatoma cells (Fuchs et al.,
2004).
In the following paragraphs specific examples of
human cancers are reported.
Breast cancer
Note
In breast cancer ASCT2 has been found over
expressed together with other proteins related to
glutamine metabolism like glutamminase and
glutamate dehydrogenase (Kim et al., 2012).
The study revealed that this metabolism is essential
for sustaining breast cancer development and that
the protein levels are different according to
different subtypes of cancer. The subtype HER2
showed the highest level of glutamine related
proteins and that the basal-like breast cancers are
more dependent on glutamine compared to luminallikeones.
Prostate cancer
Note
Tissue microarray technology (TMA) has been used
for studying ASCT2 in normal prostatic tissue, in
benign prostatic hyperplasia and in prostate
adenocarcinoma.
In particular, a negative prognosis and a shorter
time of recurrence for adenocarcinoma were
associated to hASCT2 expression. Moreover, a
more aggressive behavior of adenocarcinoma is
described (Li et al., 2003).
Other diseases
Note
Due to importance of glutamine in cell metabolism
and the chromosomal localization of SLC1A5 gene,
several association studies have been conducted to
ascertain the involvement of hASCT2 in
pathologies like cystinuria, cystic fibrosis,
schizophrenia, Hartnup disorder and pre-eclampsia.
However, no genetic associations have been
revealed.
Colorectal carcinoma
Note
The expression of ASCT2 in colorectal carcinoma
is normally associated to a decrease of percentage
in patient survival (Witte et al., 2002).
To be noted
Note
Aknowledgements: This work was supported by
funds from: Programma Operativo Nazionale [PON
01_00937] "Modelli sperimentali Biotecnologici
integrati per lo sviluppo e la selezione di molecole
di interesse per la salute dell'uomo", Ministero
Istruzione Università e Ricerca (MIUR).
Neuroblastoma and glioma
Note
Neuroblastoma are childhood tumors very often
benign. In some cases, however, neuroblastoma
became malignant. One of the biological marker of
this second category is the increased uptake of
glutamine and other neutral aminoacids via ASCT2
(Wasa et al., 2002). Human glioma C6 cells have
been demonstrated to mediate uptake of glutamine
via ASCT2 (Dolinska et al., 2003).
References
Kekuda R, Prasad PD, Fei YJ, Torres-Zamorano V, Sinha
S, Yang-Feng TL, Leibach FH, Ganapathy V. Cloning of
the sodium-dependent, broad-scope, neutral amino acid
transporter Bo from a human placental choriocarcinoma
cell line. J Biol Chem. 1996 Aug 2;271(31):18657-61
Hepatoma
Note
Hepatocell carcinoma (HCC) is the most common
malignant tumor of liver and one of the main cause
of death. A study reported that higher rate of
glutamine uptake via ASCT2 is a common feature
of six examined hepatoma cell line (Bode et al.,
2002; Fuchs et al., 2004).
Kekuda R, Torres-Zamorano V, Fei YJ, Prasad PD, Li HW,
Mader LD, Leibach FH, Ganapathy V. Molecular and
functional characterization of intestinal Na(+)-dependent
neutral amino acid transporter B0. Am J Physiol. 1997
Jun;272(6 Pt 1):G1463-72
Torres-Zamorano V, Leibach FH, Ganapathy V. Sodiumdependent homo- and hetero-exchange of neutral amino
acids mediated by the amino acid transporter ATB degree.
Biochem Biophys Res Commun. 1998 Apr 28;245(3):824-9
Lung cancer
Note
ASCT2 has been found over expressed in lung
cancer by proteomic approach and then confirmed
at molecular level. Pharmacologic and genetic
targeting of ASCT2 decreased cell growth and
viability in lung cancer cells, an effect mediated in
part by mTOR signaling (Hassanein et al., 2013).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Indiveri C, et al.
Bröer A, Brookes N, Ganapathy V, Dimmer KS, Wagner
CA, Lang F, Bröer S. The astroglial ASCT2 amino acid
transporter as a mediator of glutamine efflux. J
Neurochem. 1999 Nov;73(5):2184-94
Bröer A, Wagner C, Lang F, Bröer S. Neutral amino acid
transporter ASCT2 displays substrate-induced Na+
exchange and a substrate-gated anion conductance.
Biochem J. 2000 Mar 15;346 Pt 3:705-10
676
SLC1A5 (solute carrier family 1 (neutral amino acid transporter), member 5)
Indiveri C, et al.
Bode BP. Recent molecular advances in mammalian
glutamine transport. J Nutr. 2001 Sep;131(9 Suppl):2475S85S; discussion 2486S-7S
Fuchs BC, Bode BP. Amino acid transporters ASCT2 and
LAT1 in cancer: partners in crime? Semin Cancer Biol.
2005 Aug;15(4):254-66
Bröer S, Brookes N. Transfer of glutamine between
astrocytes
and
neurons.
J
Neurochem.
2001
May;77(3):705-19
Savas S, Schmidt S, Jarjanazi H, Ozcelik H. Functional
nsSNPs from carcinogenesis-related genes expressed in
breast tissue: potential breast cancer risk alleles and their
distribution across human populations. Hum Genomics.
2006 Mar;2(5):287-96
Bode BP, Fuchs BC, Hurley BP, Conroy JL, Suetterlin JE,
Tanabe KK, Rhoads DB, Abcouwer SF, Souba WW.
Molecular and functional analysis of glutamine uptake in
human hepatoma and liver-derived cells. Am J Physiol
Gastrointest Liver Physiol. 2002 Nov;283(5):G1062-73
Ganapathy V, Thangaraju M, Prasad PD. Nutrient
transporters in cancer: relevance to Warburg hypothesis
and beyond. Pharmacol Ther. 2009 Jan;121(1):29-40
Wasa M, Wang HS, Okada A. Characterization of Lglutamine transport by a human neuroblastoma cell line.
Am J Physiol Cell Physiol. 2002 Jun;282(6):C1246-53
Gliddon CM, Shao Z, LeMaistre JL, Anderson CM. Cellular
distribution of the neutral amino acid transporter subtype
ASCT2 in mouse brain. J Neurochem. 2009
Jan;108(2):372-83
Witte D, Ali N, Carlson N, Younes M. Overexpression of
the neutral amino acid transporter ASCT2 in human
colorectal adenocarcinoma. Anticancer Res. 2002 SepOct;22(5):2555-7
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H,
Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE,
MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan
PM, Murphy LO. Bidirectional transport of amino acids
regulates mTOR and autophagy. Cell. 2009 Feb
6;136(3):521-34
Deitmer JW, Bröer A, Bröer S. Glutamine efflux from
astrocytes is mediated by multiple pathways. J
Neurochem. 2003 Oct;87(1):127-35
Galluccio M, Pingitore P, Scalise M, Indiveri C. Cloning,
large scale over-expression in E. coli and purification of the
components of the human LAT 1 (SLC7A5) amino acid
transporter. Protein J. 2013 Aug;32(6):442-8
Dolińska M, Dybel A, Zabłocka B, Albrecht J. Glutamine
transport in C6 glioma cells shows ASCT2 system
characteristics. Neurochem Int. 2003 Sep-Oct;43(4-5):5017
Li R, Younes M, Frolov A, Wheeler TM, Scardino P, Ohori
M, Ayala G. Expression of neutral amino acid transporter
ASCT2 in human prostate. Anticancer Res. 2003 JulAug;23(4):3413-8
Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK,
Chen H, Clark JE, Alborn WE, Eisenberg R, Massion PP.
SLC1A5 mediates glutamine transport required for lung
cancer cell growth and survival. Clin Cancer Res. 2013
Feb 1;19(3):560-70
Marin M, Lavillette D, Kelly SM, Kabat D. N-linked
glycosylation and sequence changes in a critical negative
control region of the ASCT1 and ASCT2 neutral amino
acid transporters determine their retroviral receptor
functions. J Virol. 2003 Mar;77(5):2936-45
Kim S, Kim do H, Jung WH, Koo JS. Expression of
glutamine metabolism-related proteins according to
molecular subtype of breast cancer. Endocr Relat Cancer.
2013 Jun;20(3):339-48
Bungard CI, McGivan JD. Glutamine availability upregulates expression of the amino acid transporter protein
ASCT2 in HepG2 cells and stimulates the ASCT2
promoter. Biochem J. 2004 Aug 15;382(Pt 1):27-32
Pingitore P, Pochini L, Scalise M, Galluccio M, Hedfalk K,
Indiveri C. Large scale production of the active human
ASCT2 (SLC1A5) transporter in Pichia pastoris--functional
and kinetic asymmetry revealed in proteoliposomes.
Biochim Biophys Acta. 2013 Sep;1828(9):2238-46
Fuchs BC, Perez JC, Suetterlin JE, Chaudhry SB, Bode
BP. Inducible antisense RNA targeting amino acid
transporter ATB0/ASCT2 elicits apoptosis in human
hepatoma cells. Am J Physiol Gastrointest Liver Physiol.
2004 Mar;286(3):G467-78
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
This article should be referenced as such:
Indiveri C, Pochini L, Galluccio M, Scalise M. SLC1A5
(solute carrier family 1 (neutral amino acid transporter),
member 5). Atlas Genet Cytogenet Oncol Haematol. 2014;
18(9):673-677.
677
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Short Communication
USB1 (U6 snRNA biogenesis 1)
Elisa Adele Colombo
Genetica Medica, Dipartimento di Scienze della Salute, Universita degli Studi di Milano, Italy (EAC)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/USB1ID44608ch16q21.html
DOI: 10.4267/2042/54037
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
DNA/RNA
C16orf57 alias USB1 is the gene which mutations
underlie poikiloderma with neutropenia (PN)
syndrome, a rare genodermatosis with autosomic
recessive inheritance.
PN patients have an increased risk to develop
myelodysplasia and acute myeloid leukaemia in the
second decade of life.
In 2012, the protein encoded by USB1 has been
recognised to be a 2H phosphodiesterase involved
in the processing of U6 snRNA, but its action
pathway and hence role in the pathogenesis of PN
has not yet been elucidated.
Description
According to UCSC database (GRCh37/hg19,
Feb.2009), USB1 gene maps in the region between
58035277 and 58055527 bp from pter of
chromosome 16 with a centromeric-telomeric
orientation.
It spans 20 kb and is composed of seven exons
(GI:305855061; NM_024598.3) (Fig.2).
Transcription
Two physiological isoforms, generated by
alternative splicing (Fig. 2), have been detected in
normal
samples (leucocytes,
keratinocytes,
melanocytes and fibroblasts). The major transcript
of 2282 nt (isoform 1, NM_024598.3) includes all
the seven exons of the gene, while the shorter
isoform of 1217 nt (NM_001204911.1) comprises
the first three exons and an alternative terminal
fourth exon located in IVS3 (Arnold et al., 2010).
Identity
Other names: C16orf57, EC 3.1.4., hUsb1,
HVSL1, Mpn1, PN
HGNC (Hugo): USB1
Location: 16q21
Figure 1. The region on chromosome 16q21 containing USB1 and its neighbouring genes ZNF139 (zinc finger protein 319) and
MMP15 (matrix metalloproteinase 15) (UCSC database -GRCh37/hg19, Feb 2009).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
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USB1 (U6 snRNA biogenesis 1)
Colombo EA
Figure 2. Schematic representation of exon-intron structure of USB1 and the two major transcripts resulting from alternative
splicing of the two mutually exclusive exons 4.
and serine residues (H120, S122, and H208, S210)
which are essential for its catalytic activity.
Recognition of these motifs by computational
analysis of the protein sequence has predicted
USB1 belongs to the 2H phosphodiesterase
superfamily present in bacteria, archea and
eukaryotes (Colombo et al., 2012).
The protein has a globular architecture with two
juxtaposed lobes with a pseudo two-fold symmetry
separated by a central groove, which exposes the
two HLSL motifs of the active site (Fig.3).
Several additional transcripts, a few detected in
cancer samples, are reported in the Ensembl
database.
Pseudogene
No pseudogene for USB1 is known.
Protein
Description
The crystal structure of the human USB1 protein,
translated by isoform 1 mRNA has been recently
resolved (Hilcenko et al., 2013).
The main USB1 protein comprises 265 aa, while
translation of isoform 4 mRNA predicts a 186
amino acid protein with a different C-terminus.
The USB1 protein is characterized by two
tetrapeptide motifs (HLSL), containing histidine
Expression
USB1 is ubiquitously expressed in humans (Volpi
et al., 2010).
The high evolutionary conservation of the protein is
consistent with the housekeeping function of the
gene.
Figure 3. Ribbon model of the USB1 protein showing its globular symmetrical conformation with two lobes separated by a
central groove that exposes the catalytic site containing the two HLSL motifs (encircled). The terminal lobe comprises both the Nand the C-termini. Both the terminal and transit lobe consist of antiparallel β-sheets and α-helices (modified from Colombo et al.,
2012).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
679
USB1 (U6 snRNA biogenesis 1)
Colombo EA
Localisation
Mutations
A nuclear localization of USB1 has been
demonstrated in HeLa cells (Mroczek et al., 2012);
both nuclear and mitochondrial localizations have
been observed for the yeast orthologue (Glatigny et
al., 2011).
Germinal
Biallelic mutations in USB1 gene (OMIM*613276)
cause poikiloderma with neutropenia syndrome
(OMIM#604173).
To date, 19 different "loss-of-function" mutations
have been identified in 38 molecularly tested PN
patients: 7 non-sense mutations, 6 out-of-frame
deletions and 6 canonical splice site mutations. The
latter also include the only missense mutation so far
reported which however leads to exon skipping
(Volpi et al., 2010). Recurrent mutations can be
identified in patients of Navajo, Turkish and
Caucasian origin attesting a founder effect
(Colombo et al., 2012).
Function
Usb1 is a 3'-5' RNA exoribonuclease that trims the
3' end of the U6 snRNA leading to the formation of
a terminal 2',3' cyclic phosphate. This posttranscriptionally modification influences U6
stability and recycling. Evidence has been obtained
in yeast where Usb1 depletion leads to reduced
levels of U6, generalized pre-mRNA splicing
defects and shorter telomeres. In human use of PN
cell lines confirmed that U6 is a substrate of USB1,
but failed to reveal a splicing defect leaving
unsolved how PN develops (Hilcenko et al., 2012;
Mroczek et al., 2012; Shchepachev et al., 2012).
Somatic
No information is currently available on mutations
of USB1 in sporadic cancers.
Figure 4. Map across the USB1 gene of the currently known 19 mutations. Nonsense mutations are represented with a red
hexagon, deletions with a yellow star and splicing mutations with a blue triangle. The Table lists for each mutation the intragenic
position, the description (cDNA nomenclature) and the effect at the protein level.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
680
USB1 (U6 snRNA biogenesis 1)
Colombo EA
stratify the patients according to life-long cancer
risk (myelodysplasia and solid tumours).
Further studies focussing on the alternative
transcript are necessary to establish the role of
isoform 4 on PN pathogenesis and prognosis.
Implicated in
Poikiloderma with neutropenia
syndrome (PN)
Note
The disease is caused by mutations affecting the
gene represented in this entry.
The clinical presentation of PN patients partially
overlaps that of patients affected with RothmundThomson syndrome (RTS; OMIM#268400) and
dyskeratosis congenita (DC; OMIM#613987,
#613988, #613989, #615190, #224230).
Disease
Poikiloderma with neutropenia is a rare inherited
genodermatosis characterized by skin alterations
(poikiloderma, nail dystrophy, palmo-plantar
hyperkeratosis), short stature and non cyclic
neutropenia.
In infancy, neutropenia is responsible of the
recurrent infections, mainly of the respiratory
system, observed in PN patients and, later in life,
may lead to myelodysplastic syndrome and acute
myeloid leukaemia. Squamous cell carcinoma has
also been reported in PN patients.
To date, 38 out of 66 PN patients described in
literature have been molecularly tested and found to
carry biallelic mutations of the USB1 gene. Most of
the reported patients carry homozygous mutations,
attesting inheritance by descent of the same
ancestral mutation.
Prognosis
The knowledge of USB1 3D structure with the
essential amino acid motifs of the catalytic site
might enhance the prediction of USB1 mutation
effects.
All the mutations reported so far in PN patients (no.
19) interfere with USB1 function: 16 disrupt the
catalytic activity due to the loss of one or both
HLSL motifs, while the remaining 3 mutations,
although not affecting the catalytically active
tetrapeptide motifs destroy the internal symmetry of
the protein. Owing to the restricted number of
molecularly characterised PN patients no mutationphenotype correlations have emerged suitable to
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
References
Arnold AW, Itin PH, Pigors M, Kohlhase J, BrucknerTuderman L, Has C. Poikiloderma with neutropenia: a
novel C16orf57 mutation and clinical diagnostic criteria. Br
J Dermatol. 2010 Oct;163(4):866-9
Volpi L, Roversi G, Colombo EA, Leijsten N, Concolino D,
Calabria A, Mencarelli MA, Fimiani M, Macciardi F, Pfundt
R, Schoenmakers EF, Larizza L. Targeted next-generation
sequencing appoints c16orf57 as clericuzio-type
poikiloderma with neutropenia gene. Am J Hum Genet.
2010 Jan;86(1):72-6
Glatigny A, Mathieu L, Herbert CJ, Dujardin G, Meunier B,
Mucchielli-Giorgi MH. An in silico approach combined with
in vivo experiments enables the identification of a new
protein whose overexpression can compensate for specific
respiratory defects in Saccharomyces cerevisiae. BMC
Syst Biol. 2011 Oct 25;5:173
Colombo EA, Bazan JF, Negri G, Gervasini C, Elcioglu
NH, Yucelten D, Altunay I, Cetincelik U, Teti A, Del Fattore
A, Luciani M, Sullivan SK, Yan AC, Volpi L, Larizza L.
Novel C16orf57 mutations in patients with Poikiloderma
with Neutropenia: bioinformatic analysis of the protein and
predicted effects of all reported mutations. Orphanet J
Rare Dis. 2012 Jan 23;7:7
Mroczek S, Krwawicz J, Kutner J, Lazniewski M, Kuciński
I, Ginalski K, Dziembowski A. C16orf57, a gene mutated in
poikiloderma with neutropenia, encodes a putative
phosphodiesterase responsible for the U6 snRNA 3' end
modification. Genes Dev. 2012 Sep 1;26(17):1911-25
Shchepachev V, Wischnewski H, Missiaglia E, Soneson C,
Azzalin CM. Mpn1, mutated in poikiloderma with
neutropenia protein 1, is a conserved 3'-to-5' RNA
exonuclease processing U6 small nuclear RNA. Cell Rep.
2012 Oct 25;2(4):855-65
Hilcenko C, Simpson PJ, Finch AJ, Bowler FR, Churcher
MJ, Jin L, Packman LC, Shlien A, Campbell P, Kirwan M,
Dokal I, Warren AJ. Aberrant 3' oligoadenylation of
spliceosomal U6 small nuclear RNA in poikiloderma with
neutropenia. Blood. 2013 Feb 7;121(6):1028-38
This article should be referenced as such:
Colombo EA. USB1 (U6 snRNA biogenesis 1). Atlas Genet
Cytogenet Oncol Haematol. 2014; 18(9):678-681.
681
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Leukaemia Section
Short Communication
t(9;15)(p13;q24) PAX5/PML
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: January 2014
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0915p13q24ID1561.html
DOI: 10.4267/2042/54038
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Genes involved and
proteins
Short
Communication
on
t(9;15)(p13;q24)
PAX5/PML, with data on clinics, and the genes
implicated.
PAX5
Location
9p13.2
Protein
391 amino acids; from N-term to C-term, PAX5
contains: a paired domain (aa: 16-142); an
octapeptide (aa: 179-186); a partial homeodomain
(aa: 228-254); a transactivation domain (aa: 304359); and an inhibitory domain (aa: 359-391).
Lineage-specific transcription factor; recognizes the
concensus
recognition
sequence
GNCCANTGAAGCGTGAC, where N is any
nucleotide. Involved in B-cell differentiation. Entry
of common lymphoid progenitors into the B cell
lineage depends on E2A, EBF1, and PAX5;
activates B-cell specific genes and repress genes
involved in other lineage commitments. Activates
the surface cell receptor CD19 and repress FLT3.
Pax5 physically interacts with the RAG1/RAG2
complex, and removes the inhibitory signal of the
lysine-9-methylated histone H3, and induces V-toDJ rearrangements. Genes repressed by PAX5
expression in early B cells are restored in their
function in mature B cells and plasma cells, and
PAX5 repressed (Fuxa et al., 2004; Johnson et al.,
2004; Zhang et al., 2006; Cobaleda et al., 2007;
Medvedovic et al., 2011).
Identity
Note
The translocation is noted with various breakpoints
on chromosome 15, ranging from q22 to q25 (this is
reminiscent of the t(15;17) PML/RARA).
Clinics and pathology
Disease
B-cell acute lymphoblastic leukemia (B-ALL)
Epidemiology
Two cases to date, a 9-month old girl and a 1.5-year
old boy, both with a CD10+ ALL (Nebral et al.,
2007; Nebral et al., 2009).
Prognosis
A patient remains in complete remission 84 months
from diagnosis, while the other one had a testicular
relapse 2 years after diagnosis and died.
Cytogenetics
Cytogenetics morphological
The translocation was the sole abnormality.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
682
t(9;15)(p13;q24) PAX5/PML
Huret JL
PAX5/PML fusion protein.
PML
Fusion protein
Location
15q24.1
Protein
882 amino-acids (aa) and shorter isoforms with
distinct C terminus sequences; from N-term to Cterm, PML contains: a proline rich domain (aa 346); a zinc finger (RING finger type) (aa 57-92);
two zinc fingers (B-box types) (aa 124-166 and aa
183-236); a coiled coil made of hydrophobic aa
heptad repeats (aa 228-253); an interaction domain
with PER2 (aa 448-555); a nuclear localization
signal (aa 476-490); a proline rich domain (aa 504583); a serine rich domain (aa 506-540); and a
sumo interaction motif (aa 556-562).
The RING finger, B-boxes, and coiled-coil region
form a tripartite motif known as the TRIM or the
RBCC motif, and is associated with E3 ubiquitin
ligase activity.
PML is the organizer of nuclear domains called
nuclear bodies, which recruit a wide variety of
proteins, most often sumoylated. PML is involved
in DNA damage response, cell division control,
chromosome instability, and is a clock regulator via
regulation of PER2 expression. PML has proapoptotic functions, induces senescence, inhibits
angiogenesis and cell migration (Grignani et al.,
1996; Chen et al., 2012; de Thé et al., 2012).
Description
1099 amino acids. The predicted fusion protein
contains the DNA binding paired domain of PAX5
(260 aa from PAX5) and most of PML (839 aa).
References
Grignani F, Testa U, Rogaia D, Ferrucci PF, Samoggia P,
Pinto A, Aldinucci D, Gelmetti V, Fagioli M, Alcalay M,
Seeler J, Grignani F, Nicoletti I, Peschle C, Pelicci PG.
Effects on differentiation by the promyelocytic leukemia
PML/RARalpha protein depend on the fusion of the PML
protein dimerization and RARalpha DNA binding domains.
EMBO J. 1996 Sep 16;15(18):4949-58
Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E,
Busslinger M. Pax5 induces V-to-DJ rearrangements and
locus contraction of the immunoglobulin heavy-chain gene.
Genes Dev. 2004 Feb 15;18(4):411-22
Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell
AL, Thomas-Tikhonenko A, Schatz DG, Calame K. B cellspecific loss of histone 3 lysine 9 methylation in the V(H)
locus depends on Pax5. Nat Immunol. 2004 Aug;5(8):85361
Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams
GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD.
Transcription factor Pax5 (BSAP) transactivates the RAGmediated V(H)-to-DJ(H) rearrangement of immunoglobulin
genes. Nat Immunol. 2006 Jun;7(6):616-24
Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5:
the guardian of B cell identity and function. Nat Immunol.
2007 May;8(5):463-70
Result of the chromosomal
anomaly
Nebral K, König M, Harder L, Siebert R, Haas OA, Strehl
S. Identification of PML as novel PAX5 fusion partner in
childhood acute lymphoblastic leukaemia. Br J Haematol.
2007 Oct;139(2):269-74
Hybrid gene
Nebral K, Denk D, Attarbaschi A, König M, Mann G, Haas
OA, Strehl S. Incidence and diversity of PAX5 fusion
genes in childhood acute lymphoblastic leukemia.
Leukemia. 2009 Jan;23(1):134-43
Description
Fusion of PAX5 exon 6 to PML exon 2.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
683
t(9;15)(p13;q24) PAX5/PML
Huret JL
Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a
master regulator of B cell development and
leukemogenesis. Adv Immunol. 2011;111:179-206
de Thé H, Le Bras M, Lallemand-Breitenbach V. The cell
biology of disease: Acute promyelocytic leukemia, arsenic,
and PML bodies. J Cell Biol. 2012 Jul 9;198(1):11-21
Chen RH, Lee YR, Yuan WC. The role of PML
ubiquitination in human malignancies. J Biomed Sci. 2012
Aug 30;19:81
This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Huret JL. t(9;15)(p13;q24) PAX5/PML. Atlas
Cytogenet Oncol Haematol. 2014; 18(9):682-684.
684
Genet
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Leukaemia Section
Short Communication
t(1;9)(p13;p12) PAX5/HIPK1
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0109p13p12ID1557.html
DOI: 10.4267/2042/54039
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
degradation of proteins) (aa 892-972), SUMO
interaction motifs, required for nuclear localization
and kinase activity (aa 902-926), a domain
interacting with DAB2IP/MAP3K5 (aa 973-1209),
a histidine-rich region (aa 1086-1154), and a
tyrosine-rich region (aa 1175-1209) (YH region).
The lysine residues at the sumoylation motifs are
the following: K25, K317, K440, K556, and K1202
(Kim et al., 1998; Li et al., 2005; Swiss-Prot).
First identified as a nuclear serine/threonine kinase.
Homeodomain-interacting protein kinase. HIPK1
positively or negatively modulate signaling
pathways controlling cell proliferation and/or
apoptosis (review in Rinaldo et al., 2008). HIPK1
and HIPK2 act cooperatively as corepressors in the
transcriptional activation of angiogenic genes,
including MMP10 (11q22.2) and VEGFA (6p21.1),
that are critical for the early stage of vascular
development (Shang et al., 2013).
HIPK1 regulates the p53 signaling pathway.
PARK7 (also called DJ-1, 1p36.23), a protein also
linked to the p53 signaling pathway, is able to
induce HIPK1 degradation.
HIPK1 directly phophorylates TP53 on its serine15. Serine 15 phosphorylation induces a rise in
CDKN1A (p21, 6p21.2) expression and cell cycle
arrest (Rey et al., 2013).
HIPK1 phosphorylates DAXX (6p21.32), a protein
which interacts with PML (15q24.1), the organizer
of nuclear bodies (Ecsedy et al., 2003), and which
relocalizes from the nucleus to the cytoplasm in
response to stress. During glucose deprivation, a
pathway involving MAP3K5 (also called ASK1,
6q23.3), -> MAP2K4 (SEK1, 17p12) -> MAPK8
(JNK1, 10q11.22) -> HIPK1 is activated, and
DAXX is relocated in the cytoplasm (Song and
Lee, 2003).
Abstract
Short
communication
on
t(1;9)(p13;p12)
PAX5/HIPK1, with data on clinics, and the genes
implicated.
Clinics and pathology
Disease
B-cell acute lymphoblastic leukemia (B-ALL)
Epidemiology
Only one case to date, a 3-year old boy with a
CD10+ ALL (Nebral et al., 2009).
Prognosis
The patient was noted at an intermediate risk, and
was in complete remission 6 months after
diagnosis.
Genes involved and
proteins
HIPK1
Location
1p13.2
Protein
1210 amino acids (aa). From N-term to C-term,
contains a protein kinase domain (aa 190-518), a
nucleotide binding motif (aa 196-204), a domain
interacting with DAB2IP (AIP1, or AF9q34,
9q33.2) (aa 518-889), a nuclear localization signal
(aa 844-847), a region interacting with TP53 (aa
885-1093), a nuclear speckle retention signal (aa
887-992), (corresponding to aa 860-967 in HIPK2),
a PEST domain (enriched in proline (P), glutamate
(E), serine (S), and threonine (T), expedite the
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
685
t(1;9)(p13;p12) PAX5/HIPK1
Huret JL
t(1;9)(p13;p13) PAX5/HIPK1 fusion protein.
TNF (TNF-alpha, 6p21.33) induces desumoylation
and cytoplasm translocation of HIPK1 leading to
apoptosis (Li et al., 2005). HIPK1 and HIPK2 bind
HOX genes homeodomains and regulate their
expression, as well as PAX1 (20p11.22) and PAX3
(2q36.1) transcription (Isono et al., 2006). HIPK1
and HIPK2 phosphorylates EP300 (22q13.2) and
RUNX1
(21q22.12)
during
embryonic
development, and Hipk1/Hipk2-deficient mice
show defective definitive hematopoiesis (Aikawa et
al., 2006). HIPK1 phosphorylates MYB (6q23.3), a
transcriptional activator essential for the
establishment of haemopoiesis, and causes
repression of MYB activation (Matre et al., 2009).
HIPK1 interacts with DVL1 (1p36.33) and TCF3
(E2A, 19p13.3) and regulates Wnt/b-catenin target
genes during early embryonic development (Louie
et al., 2009). HIPK1 is highly overexpressed in
colorectal carcinomas compared with healthy
mucosa. The highest peak of HIPK1 expression
occurred at early stages and decreased in latter
stages. HIPK1 appeared to be induced as a defense
mechanism to fight against intern deregulations and
stressful conditions, rather than produced by the
cancer cells as an indispensable factor for tumor
evolution (Rey et al., 2013). HIPK1 is expressed
only in invasive breast cancer cells with three
different subcellular localization, associated with
different tumor histopathologic characteristics (Park
et al., 2012).
Protein
391 amino acids; from N-term to C-term, PAX5
contains: a paired domain (aa: 16-142); an
octapeptide (aa: 179-186); a partial homeodomain
(aa: 228-254); a transactivation domain (aa: 304359); and an inhibitory domain (aa: 359-391).
Lineage-specific transcription factor; recognizes the
concensus
recognition
sequence
GNCCANTGAAGCGTGAC, where N is any
nucleotide.
Involved in B-cell differentiation. Entry of common
lymphoid progenitors into the B cell lineage
depends on E2A, EBF1, and PAX5; activates B-cell
specific genes and repress genes involved in other
lineage commitments. Activates the surface cell
receptor CD19 and repress FLT3. Pax5 physically
interacts with the RAG1/RAG2 complex, and
removes the inhibitory signal of the lysine-9methylated histone H3, and induces V-to-DJ
rearrangements. Genes repressed by PAX5
expression in early B cells are restored in their
function in mature B cells and plasma cells, and
PAX5 repressed (Fuxa et al., 2004; Johnson et al.,
2004; Zhang et al., 2006; Cobaleda et al., 2007;
Medvedovic et al., 2011).
PAX5
Hybrid gene
Location
9p13.2
Description
Fusion of PAX5 exon 5 to HIPK1 exon 9.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Result of the chromosomal
anomaly
686
t(1;9)(p13;p12) PAX5/HIPK1
Huret JL
homeodomain-interacting protein kinases hipk1 and hipk2
in the mediation of cell growth in response to
morphogenetic and genotoxic signals. Mol Cell Biol. 2006
Apr;26(7):2758-71
Fusion protein
Description
751 amino acids. The predicted fusion protein
contains the DNA binding paired domain of PAX5
and the nuclear localization signal, the region
interacting with TP53, the nuclear speckle retention
signal, the PEST domain, the SUMO interaction
motifs,
the
domain
interacting
with
DAB2IP/MAP3K5, and theYH region from HIPK1.
Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams
GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD.
Transcription factor Pax5 (BSAP) transactivates the RAGmediated V(H)-to-DJ(H) rearrangement of immunoglobulin
genes. Nat Immunol. 2006 Jun;7(6):616-24
Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5:
the guardian of B cell identity and function. Nat Immunol.
2007 May;8(5):463-70
References
Rinaldo C, Siepi F, Prodosmo A, Soddu S. HIPKs: Jack of
all trades in basic nuclear activities. Biochim Biophys Acta.
2008 Nov;1783(11):2124-9
Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y.
Homeodomain-interacting protein kinases, a novel family
of co-repressors for homeodomain transcription factors. J
Biol Chem. 1998 Oct 2;273(40):25875-9
Louie SH, Yang XY, Conrad WH, Muster J, Angers S,
Moon RT, Cheyette BN. Modulation of the beta-catenin
signaling pathway by the dishevelled-associated protein
Hipk1. PLoS One. 2009;4(2):e4310
Ecsedy JA, Michaelson JS, Leder P. Homeodomaininteracting protein kinase 1 modulates Daxx localization,
phosphorylation, and transcriptional activity. Mol Cell Biol.
2003 Feb;23(3):950-60
Matre V, Nordgård O, Alm-Kristiansen AH, Ledsaak M,
Gabrielsen OS. HIPK1 interacts with c-Myb and modulates
its activity through phosphorylation. Biochem Biophys Res
Commun. 2009 Oct 9;388(1):150-4
Song JJ, Lee YJ. Role of the ASK1-SEK1-JNK1-HIPK1
signal in Daxx trafficking and ASK1 oligomerization. J Biol
Chem. 2003 Nov 21;278(47):47245-52
Nebral K, Denk D, Attarbaschi A, König M, Mann G, Haas
OA, Strehl S. Incidence and diversity of PAX5 fusion
genes in childhood acute lymphoblastic leukemia.
Leukemia. 2009 Jan;23(1):134-43
Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E,
Busslinger M. Pax5 induces V-to-DJ rearrangements and
locus contraction of the immunoglobulin heavy-chain gene.
Genes Dev. 2004 Feb 15;18(4):411-22
Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a
master regulator of B cell development and
leukemogenesis. Adv Immunol. 2011;111:179-206
Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell
AL, Thomas-Tikhonenko A, Schatz DG, Calame K. B cellspecific loss of histone 3 lysine 9 methylation in the V(H)
locus depends on Pax5. Nat Immunol. 2004 Aug;5(8):85361
Park BW, Park S, Koo JS, Kim SI, Park JM, Cho JH, Park
HS. Homeodomain-interacting protein kinase 1 (HIPK1)
expression in breast cancer tissues. Jpn J Clin Oncol.
2012 Dec;42(12):1138-45
Li X, Zhang R, Luo D, Park SJ, Wang Q, Kim Y, Min W.
Tumor necrosis factor alpha-induced desumoylation and
cytoplasmic translocation of homeodomain-interacting
protein kinase 1 are critical for apoptosis signal-regulating
kinase 1-JNK/p38 activation. J Biol Chem. 2005 Apr
15;280(15):15061-70
Rey C, Soubeyran I, Mahouche I, Pedeboscq S, Bessede
A, Ichas F, De Giorgi F, Lartigue L. HIPK1 drives p53
activation to limit colorectal cancer cell growth. Cell Cycle.
2013 Jun 15;12(12):1879-91
Shang Y, Doan CN, Arnold TD, Lee S, Tang AA, Reichardt
LF, Huang EJ. Transcriptional corepressors HIPK1 and
HIPK2 control angiogenesis via TGF-β-TAK1-dependent
mechanism. PLoS Biol. 2013;11(4):e1001527
Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y,
Schmitz ML, Koseki H, Kitabayashi I. Roles of HIPK1 and
HIPK2 in AML1- and p300-dependent transcription,
hematopoiesis and blood vessel formation. EMBO J. 2006
Sep 6;25(17):3955-65
This article should be referenced as such:
Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M,
Nakagawara A, Koseki H. Overlapping roles for
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Huret JL. t(1;9)(p13;p12) PAX5/HIPK1. Atlas Genet
Cytogenet Oncol Haematol. 2014; 18(9):685-687.
687
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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OPEN ACCESS JOURNAL
Solid Tumour Section
Short Communication
Lung: t(6;12)(q22;q14.1) LRIG3/ROS1 in lung
adenocarcinoma
Kana Sakamoto, Yuki Togashi, Kengo Takeuchi
Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer
Research, Tokyo, Japan (KS, YT, KT)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0612q22q14inLungID6496.html
DOI: 10.4267/2042/54040
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
UFT. Although not administered in this case,
Crizotinib and other ALK inhibitors have been
reported to be effective in lung cancers with ROS1
translocations (Bergethon et al., 2012; Shaw et al.,
2012).
Abstract
Short communication on t(6;12)(q22;q14.1)
LRIG3/ROS1 in lung adenocarcinoma with data on
clinics.
Prognosis
Clinics and pathology
With 5 years of follow-up, the patient was alive
without relapse.
Disease
Lung adenocarcinoma
Genes involved and
proteins
Epidemiology
ROS1 translocations are found in 0.9 to 1.7% of
non small cell lung carcinomas and the majority of
the cases are adenocarcinoma (Bergethon et al.,
2012; Davies et al., 2012; Takeuchi et al., 2012).
Multiple fusion partners have been identified and
LRIG3 is one of them. As for LRIG3-ROS1, only
one case, a 57-year-old Japanese male patient, has
been reported to date (Takeuchi et al., 2012).
LRIG3
Location
12q14.1
DNA / RNA
Leucine-Rich Repeats And Immunoglobulin-Like
Domains Protein 3.
Clinics
ROS1
The patient had a 5 pack year of smoking history
and was diagnosed as having stage 1A lung
adenocarcinoma.
Location
6q22
DNA / RNA
C-Ros Oncogene 1, Receptor Tyrosine Kinase.
Pathology
This case showed moderately differentiated
micropapillary pattern. A mucinous cribriform
pattern which is frequently seen in cancers with
kinase fusions was not found. This case was
negative for EGFR and KRAS mutations as with
the most cases harboring ROS1 gene fusions.
Result of the chromosomal
anomaly
Hybrid Gene
Treatment
Transcript
LRIG3-ROS1 fusion transcript was detected.
The primary tumor was surgically removed and the
patient received post-operative chemotherapy with
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
688
Lung: t(6;12)(q22;q14.1) LRIG3/ROS1 in lung adenocarcinomaSakamoto K, et al.
A. The schematic structure of LRIG3, ROS1, and LRIG3-ROS1 proteins and the cDNA sequence around the fusion point:
Exon 16 of LRIG3 fused to exon 35 of ROS1. The break point of ROS1 allows the resulting fusion protein to retain the kinase
domain (red). LRIG3 contains a transmembrane domain (orange). B: RT-PCR confirmation of LRIG3-ROS1 fusion: Lane M
and N represent the size standard (20-bp ladder) and the non-template control, respectively. C. Fusion FISH analysis: A fusion
signal (yellow) was observed in consequence of the fusion of LRIG3 (red) and ROS1 (green).
Detection
A 218 bp cDNA fragment harboring the fusion
point can be detected with LRIG3 forward primer
(5'-ACACAGATGAGACCAACTTGC-3')
and
ROS1
reverse
primer
(5'CACTGTCACCCCTTCCTTG-3').
Oncogenesis
The oncogenicity of LRIG3-ROS1 fusion was
proven in a focus formation assay and a nude
mouse tumorigenicity assay (Takeuchi et al., 2012).
Fusion Protein
Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM,
McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A,
Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak
EL, Clark JW, Carbone DP, Ji H, Engelman JA, MinoKenudson M, Pao W, Iafrate AJ. ROS1 rearrangements
define a unique molecular class of lung cancers. J Clin
Oncol. 2012 Mar 10;30(8):863-70
References
Description
The fusion protein encompasses the constitutive
activation of ROS1 tyrosine kinase.
However, the mechanism of it is largely unknown.
The role of LRIG3 here has not been clarified.
LRIG3 protein does not contain a coiled-coil
domain as in the case with most of the other ROS1
fusion partners (Takeuchi et al., 2012).
In respect of the downstream signaling, several
growth and survival signaling pathways which are
common to other receptor tyrosine kinases have
been shown to be involved.
These
include
PI3K/AKT,
JAK/STAT3,
RAS/MAPK/ERK, VAV3, and SHP-1 and SHP-2
pathways (Chin et al., 2012; Davies and Doebele,
2013).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Chin LP, Soo RA, Soong R, Ou SH. Targeting ROS1 with
anaplastic lymphoma kinase inhibitors: a promising
therapeutic strategy for a newly defined molecular subset
of non-small-cell lung cancer. J Thorac Oncol. 2012
Nov;7(11):1625-30
Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL,
Berge EM, Terracciano LM, Cappuzzo F, Incarbone M,
Roncalli M, Alloisio M, Santoro A, Camidge DR, VarellaGarcia M, Doebele RC. Identifying and targeting ROS1
gene fusions in non-small cell lung cancer. Clin Cancer
Res. 2012 Sep 1;18(17):4570-9
Shaw AT, Camidge DR, Engelman JA, Solomon BJ, Kwak
EL, Clark JW, Salgia R, Shapiro G, Bang YJ, Tan W, Tye
689
Lung: t(6;12)(q22;q14.1) LRIG3/ROS1 in lung adenocarcinomaSakamoto K, et al.
L, Wilner KD, Stephenson P, Varella-Garcia M, Bergethon
K, Iafrate AJ, Ou SHI.. Clinical activity of crizotinib in
advanced non-small cell lung cancer (NSCLC) harboring
ROS1 gene rearrangement. J Clin Oncol 2012;30:(suppl;
abstr 7508).
Davies KD, Doebele RC.. Molecular pathways: ROS1
fusion proteins in cancer. Clin Cancer Res. 2013 Aug
1;19(15):4040-5. doi: 10.1158/1078-0432.CCR-12-2851.
Epub 2013 May 29. (REVIEW)
This article should be referenced as such:
Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S,
Hatano S, Asaka R, Hamanaka W, Ninomiya H et al.. RET,
ROS1 and ALK fusions in lung cancer. Nat Med. 2012 Feb
12;18(3):378-81. doi: 10.1038/nm.2658.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Sakamoto K, Togashi Y, Takeuchi K. Lung:
t(6;12)(q22;q14.1) LRIG3/ROS1 in lung adenocarcinoma.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9):688690.
690
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Deep Insight Section
The tumour suppressor function of the
scaffolding protein spinophilin
Denis Sarrouilhe, Véronique Ladeveze
Laboratoire de Physiologie Humaine, Faculte de Medecine et Pharmacie, Universite de Poitiers, 6 rue
de la Miletrie, Bat D1, TSA 51115, 86073 Poitiers, Cedex 9, France (DS), Laboratoire de Genetique
Moleculaire de Maladies Rares, Universite de Poitiers, UFR SFA, Pole Biologie Sante, Bat B36, TSA
51106, 86073 Poitiers, Cedex 9, France (VL)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Deep/SpinophilinID20133.html
DOI: 10.4267/2042/54041
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Spinophilin is a scaffolding protein with modular domains that govern its interaction with a large number of
cellular proteins. The Spinophilin gene locus is localized at chromosome 17q21, a chromosomal region
frequently affected by genomic instability in different human tumours. The scaffolding protein interacts with the
tumour-suppressor ARF which has suggested a role for Spinophilin in cell growth. More recently, in vitro and in
vivo studies demonstrated that Spinophilin is a new tumour suppressor acting via the regulation of pRb. A clear
downregulation of Spinophilin is found in several human cancer types. Moreover, Spinophilin loss is associated
with a poor patient prognosis in carcinoma. Currently, there are controversial findings regarding a functional
relationship between Spinophilin and p53 in cell cycle regulation and in carcinogenesis. Here we present the
available data regarding Spinophilin function as a tumour suppressor.
Actin-Binding proteIN), and the latter was further
identified as Spn (Nakanishi et al., 1997). Spn is
expressed ubiquitously while neurabin 1 is
expressed almost exclusively in neuronal cells. Spn
exhibits the characteristics of scaffolding proteins
with multiple protein interaction domains (Allen et
al., 1997; Sarrouilhe et al., 2006). Scaffolding
proteins link signalling enzymes, substrates and
potential effectors (such as channels, receptors) into
a multiprotein signalling complex that may be
anchored to the cytoskeleton. In the years after this
discovery, the spectrum of Spn partners and
functions has expanded but has remained mostly in
the field of neurobiology (Sarrouilhe et al., 2006).
Spn has been implicated in the pathophysiology of
several central nervous system (CNS) diseases,
among which are Parkinson's disease, schizophrenia
and mood disorders (Law et al., 2004; Brown et al.,
2005). Spn is highly enriched at the synaptic
membrane in dendritic spines, the site of excitatory
neurotransmission and thus may control PP1
functions during synaptic activity (Ouimet et al.,
Key words
CaSR, G protein-coupled receptor, signaling
1- Introduction
Protein phosphatase 1 (PP1) is a widespread
expressed phosphoSerine/phosphoThreonine PP
involved in many cellular processes (Ceulemans
and Bollen, 2004). There are four isoforms of PP1
catalytic subunit (PP1c): PP1α, PP1β, PP1γ1 and
PP1γ2, the latter two arising through alternative
splicing (Sasaki et al., 1990). PP1c can form
complexes with up to 50 regulatory subunits
converting the enzyme into many different forms,
which have distinct substrates specificities,
restricted subcellular locations and diverse
regulations (Cohen, 2002). In late 1990s, a novel
PP1c binding protein that is a potent modulator of
PP1 activity was characterized in rat brain and
named spinophilin (Spn) (Allen et al., 1997). In the
same time, two novel actin filament-binding
proteins were purified from rat brain and named
neurabin 1 and neurabin 2 (NEURal tissue-specific-
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
691
The tumour suppressor function of the scaffolding protein spinophilin
2004). Spn regulates plasticity at the postsynaptic
density (PSD) by targeting PP1c to α-amino-3hydroxy-5-methylisoxazole-4-propionic
acid
(AMPA) and N-methyl-D-aspartic acid (NMDA)
receptors, promoting their down regulation by
dephosphorylation and thus regulating the
efficiency
of
post-synaptic
glutamatergic
neurotransmission. Spn and neurabin1 play
different roles in hippocampal and striatal synaptic
plasticity. Spn is involved in long-term depression
(LTD) but not in long-term potentiation (LTP)
whereas neurabin 1 contributes selectively to LTP
but not LTD (Feng et al., 2000; Allen et al., 2006;
Wu et al., 2008). In the same way, the two
scaffolding proteins form a functional pair of
opposing regulators that reciprocally regulate
signalling intensity by some seven-transmembrane
domain receptors (Wang et al., 2007). Thus, an
emerging notion is that Spn and neurabin 1 may
differentially affect their target proteins and
perform quite distinctive function in cell.
Morphological studies have established that Spn is
enriched at plasma membrane of cells although the
protein is also expressed widely throughout the
cytoplasm (Smith et al., 1999; Richman et al., 2001;
Tsukada et al., 2003). Spn, which is expressed
partly in the nucleus in mammalian cells, interacts
in vitro and in vivo with the tumor-suppressor ARF
(Alternative Reading Frame). Moreover, a role for
Spn in cell growth was suggested, and this effect
was enhanced by the interaction between Spn and
ARF (Vivo et al., 2001). More recent studies
showed that Spn is a new tumour suppressor and
that a clear downregulation of this protein is found
in several cancer types (Carnero, 2012).
Furthermore, Spn loss is associated with poor
patient prognosis in carcinomas (Sarrouilhe, 2014).
This review aims to outline the state of knowledge
regarding Spn function in carcinogenesis.
domains, a PSD95/DLG/zo-1 (PDZ) and three
coiled-coil domains. Figure 2 provides a schematic
diagram of the main Spn structural domains.
In the five species of the Figure 1, the coiled-coil
region has high identity with only one variation
detected in Cricetulus griseus. The PDZ domain,
the pentapeptide motif of PP1c -binding domain
and the sextapeptide allowing the binding
selectivity of PP1c isoforms, present the same
identity. Moreover, the phosphoSer are conserved
except the Ser-177 which is only detected in rat.
Being not detected in mouse (G as in primates),
Ser-177 is not a consequence of the rodent-specific
high substitution rate.
Spn has been isolated from rat brain as a protein
interacting with F-actin (Satoh et al., 1998). Its Factin-binding domain determined to be amino
acids 1-154 is both necessary and sufficient to
mediate actin polymers binding and cross-linking.
Nuclear Magnetic Resonance (NMR) and circular
dichroism (CD) spectroscopy studies showed that
Spn F-actin-binding domain is intrinsically
unstructured and that upon binding to F-actin it
adopts a more ordered structure (a phenomenom
also called folding-upon-binding). Another actin
binding property, namely a F-actin pointed end
capping activity was recently proposed for this
domain (Schüler and Peti, 2007). Spn, PP1c and Factin can form a trimeric complex in vitro.
A receptor-interacting domain, located between
amino acids 151-444, interacts with the third
intracellular loop (3i) of various seven
transmembrane domain receptors (Smith et al.,
1999; Richman et al., 2001) such as the dopamine
D2 receptor (D2R), some subtypes of the αadrenergic (AR) and muscarinic-acetylcholine (mAchR) receptors.
The primary PP1c-binding domain is located
within residues 417-494 of Spn and this domain
contains a pentapeptide motif (R-K-I-H-F) between
amino acids 447 and 451 that is conserved in other
PP1c regulatory subunits. A domain C-terminal to
this canonical PP1-binding motif, located within
amino acids 464 and 470, is essential for PP1
isoform selectivity in vitro and for selective
targeting in cells (Carmody et al., 2008).
Recently, the 3-dimentional structure of the
PP1/Spn holoenzyme was determined. Spn is an
unstructured protein in its unbound state that
undergoes a folding transition upon interaction with
PP1c into a single, stable conformation. The
scaffolding protein binds to PP1c and blocks some
potential substrate binding sites without altering its
active site, then didacting substrate specificity of
the enzyme (Ragusa et al., 2010). A further study
showed that the PP1/Spn holoenzyme is dynamic in
solution.
2- Spinophilin structure
The primate (homo sapiens and Callithrix jacchus)
Spn proteins contain 815 amino acids whereas the
rodent Spn (rattus norvegicus and mus musculus)
have 817amino acids. These sequences are very
similar, with few amino acids substitutions
compared to the human sequence in C-terminus but
the N-terminus is more variable even if the
variability is weak (Figure 1). Consequently, few
differences are observed when we compared these
sequences to the human one: the rat and human Spn
proteins share 96% sequence identity (Allen et al.,
1997; Vivo et al., 2001). In Cricetulus griseus, the
sequence is shorter than the others: 631amino acids.
Gene analysis and biochemical approaches have
contributed to define in Spn a number of distinct
modular domains. This 130 kDa protein contains
one F-actin-, a receptor- and a PP1c- binding
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The tumour suppressor function of the scaffolding protein spinophilin
Sarrouilhe D, Ladeveze V
Figure 1. Alignment of amino acid sequences of spinophilin in different species. Blast and Align programs via UniProt site
were used.
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The tumour suppressor function of the scaffolding protein spinophilin
Sarrouilhe D, Ladeveze V
Figure 2. Schematic drawing of spinophilin structure. The canonical protein phosphatase 1-binding domain is located within
amino acids 447 and 451 in spinophilin.
signalling protein (like RGS8), guanine nucleotide
exchange factors (like kalirin 7), membrane
receptors [like the α-ARs, m-AChRs, D2R, δ- and
µ-opioid receptors (OR) and cholecystokinin (CCK)
receptors], and other proteins like ions channels
[The transient receptor potential canonical (TRPC),
the type 2 ryanodine receptor (RYR2)], TGN38 and
ARF.
Shortly after the cloning of Spn as a novel PP1cbinding protein, another laboratory cloned this
protein based on its ability to bind to F-actin (Satoh
et al., 1998).
Recombinant Spn and neurabin 1 interacted with
each other when co-expressed in cells. On the other
hand, recombinant Spn was shown to form
homodimers, trimers or tetramers by interaction
between coiled-coil domains. Spn homomeric
complexes are thought to contribute to its actincross-linking activity (Satoh et al., 1998).
Doublecortin (DCX) is a microtubule-associated
protein that can induce microtubule polymerization
and
stabilize
microtubules
filaments.
Immunoprecipitation experiments with brain
extracts showed that Spn and DCX interact
incultured cells (Tsukada et al., 2003).
In vitro assays showed that DCX also binds to and
bundles F-actin, suggesting that the protein crosslinks microtubules and F-actin.
The distribution of DCX between the two
cytoskeletons can be regulated by Spn and by
phosphorylation of DCX and it was proposed that
Spn could localize and enhance the binding of
phosphorylated DCX to F-actin (Tsukada et al.,
2005).
Several studies have shown that Spn preferentially
binds to PP1γ1 and PP1α isoforms in brain extracts
(MacMillan et al., 1999; Terry-Lorenzo et al., 2002;
Carmody et al., 2004).
GST-Spn fusion proteins containing the PP1cbinding domain potently inhibit PP1 enzymatic
activity in vitro (Allen et al., 1997; Colbran et al.,
2003).
However, it was recently shown that instead of
inhibiting PP1c directly, Spn regulated enzymatic
activity by directing its substrate specificity
(Ragusa et al., 2010).
Spn can associate with the tyrosine phosphatase
SHP-1 and the complex modulates platelet
The complex adopts a significant more extended
conformation in solution than in the crystal
structure. This is the result of a flexible linker
(ramino acids 490-494) between the PP1c-binding
and the PDZ domains. The four residue flexibility
is likely important for Spn biological role (Ragusa
et al., 2011).
Spn also contains a single consensus sequence in
PDZ, amino acids 494-585 (Allen et al., 1997). The
structure of the Spn PDZ domain has been recently
solved by NMR spectroscopy. The PDZ domain
directly binds to carboxy-terminal peptides derived
from glutamatergic AMPA and NMDA receptors
(Kelker et al., 2007).
Sequence analysis predicted that the carboxyterminal region of Spn (amino acids 664-814)
forms 3 coiled-coil domains. Neurabins were
observed as multimeric forms in vitro and in vivo.
Spn and neurabin 1 homo- and hetero-dimerize via
their
carboxy-terminal
coiled-coil
domains
(MacMillan et al., 1999; Oliver et al., 2002).
Consensus sequences for phosphorylation by
several protein kinases (PK), including cAMPdependent PK (PKA), Ca2+/calmodulin-dependent
PK II (CaMKII), cyclin-dependent PK5 (Cdk5),
extracellular-signal regulated PK (ERK) and protein
tyrosine kinases were observed in Spn. Two major
sites of phosphorylation for PKA (Ser-177 not
conserved in human, and Ser-94) and two others
sites for CaMKII phosphorylation (Ser-100 and
Ser-116) were located within and near the F-actinbinding domain of Spn. The protein is
phosphorylated in intact cells by PKA at Ser-94 and
Ser-177 and by CaMKII at Ser-100 (Hsieh-Wilson
et al., 2003; Grossman et al., 2004). Moreover,
neurabins can be phosphorylated in vitro and in
intact cells by Cdk5 on Ser-17 and ERK2 (MAPK1)
on Ser-15 and Ser-205, phosphoSer-17 being
abundant in neuronal cells (Futter et al., 2005).
Several potential tyrosine phosphorylation sites lie
within the coiled-coil regions, within a region
adjacent to the PDZ domain and within the
receptor-interacting domain.
3- The Spinophilin interactome
Spn interactome includes cytoskeletal molecules
(F-actin, doublecortin, neurabin 1, Spn), enzymes
(like PP1 and CaMKII), regulator of G-protein
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The tumour suppressor function of the scaffolding protein spinophilin
nervous system. Spn was identified with other
dendritic spines proteins as a protein partner of
TRPC5 and TRPC6 channels (Goel et al., 2005). In
cardiomyocytes, Spn targets PP1 to RYR2 via
binding to a leucine zipper (LZ) motif of RYR2 and
a LZ motif on Spn (amino acids 300-634) causing
dephosphorylation and modulation of the channel
activity (Marx et al., 2001).
TGN38 is an integral membrane protein that
constitutively cycles between the trans-Golgi
network (TGN) and plasma membrane via
endosomal intermediates. TGN38 directly interacts
with the coiled-coil region of Spn, preferentially
with the dimerized proteins (Stephens and Banting,
1999). Spn has been shown to interact with the
nuclear protein ARF in mammalian cells. The
amino acids sequence 605-726, of the coiled-coil
region of Spn, seems to be involved and an intact
ARF N-terminal region (amino acids 1-65) is
necessary for this interaction (Vivo et al., 2001).
activation by sequestering RGS10 and RGS18. The
sequence surrounding the phosphorylation site
Y398 in Spn fits a consensus ITIM sequence
(I/V/L/SxY(p)xx(I/V/L) and forms a binding site
for SHP1 (Ma et al., 2012). p70S6K is a mitogenactivated PK that regulates cell survival and
growth. p70S6K interaction with neurabin 1
(Burnett et al., 1998) and Spn was demonstrated
(Allen and Greengard, unpublished observation).
The interaction implicates the PDZ domain of
neurabins and the carboxyl-terminal five amino
acids of the PK. CaMKII directly and indirectly
associates with N- and C-terminal domains of Spn.
Thus, Spn can target CaMKII to F-actin as well as
target PP1 to CaMKII (Baucum et al., 2012).
Regulator of G-protein signalling (RGS) proteins
play a crucial role in the shutting off process of Gprotein-mediated responses (Ishii and Kurachi,
2003). Spn binds to different members of the RGS
family (Wang et al., 2005; Wang et al., 2007). For
example, Spn binds to through the 391-545 amino
acids of the scaffolding protein and the 6-9 amino
acids of the N-terminus of RGS8 (Fujii et al.,
2008).
Guanine nucleotide exchange factors (GEF)
activate small G protein through the exchange of
bound GDP for GTP. Several GEF were shown to
interact with Spn. For example, Spn, through its
carboxy-terminus containing the PDZ and coiledcoil domains interacts with kalirin-7, the neuronal
GEF for Rac1 (Penzes et al., 2001).
Spn interacts with some receptors that belong to the
superfamily of GPCRs, mainly in the CNS. Using
the 3i loop of the D2R, Spn has been identified as a
protein that specifically associates with the receptor
in rat hippocampal (Smith et al., 1999). The 3i
loops of α2A-AR, α2B-AR, and α2C-AR subtypes
interact also with Spn (Richman et al., 2001). More
recently, it has been shown that the α1B-AR interacts
with Spn in vitro (Wang et al., 2005). In the
cerebellum, Spn can bind to the M1-m-AChR
using the receptor binding domain of the
scaffolding protein (Fujii et al., 2008). Spn can also
interact with the M2- and M3-m-AchRs but the
binding ability to the M3-m-AChR seems to be
weaker than those to the M1- and M2-m-AChR
(Wang et al., 2007; Kurogi et al., 2009). Moreover,
Spn binds to the 3i loop of CCKA and CCKB
receptors (Wang et al., 2007). The receptor binding
domain of Spn also associates with the 3i loop and
a conserved region of the C-terminal tails of δ- and
µ-OR (Fourla et al., 2012). Spn also interacts with
the ionotropic NMDA and AMPA-type glutamate
receptors. PDZ domain directly binds to GluR2-,
GluR3- (AMPA receptor) and NR1C2'-, NR2A/Band NR2C/D- (NMDA receptor) derived peptides
(Kelker et al., 2007).
TRPC ion channels are Ca2+ /cation selective
channels that are highly expressed in the central
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4- Spinophilin as a tumour
suppressor
The Spn gene locus is located on chromosome 17 at
position 17q21.33, a cytogenetic area frequently
associated with microsatellite instability and loss of
heterozygosity (LOH) observed in different human
tumours. This region contains a relatively high
density of known (such as BRCA1), putative as well
as several yet-unidentified candidate tumour
suppressor genes located distal to BRCA1 locus.
Thus, several studies in breast and ovarian
carcinomas have suggested the presence of an
unknown tumour suppressor gene in the area that
includes the Spn locus. However, despite these
preliminary genetic correlations, no in-depth
analysis of the role of Spn as a tumour suppressor
has been made.
The Amancio Carnero laboratory from the Instituto
de Biomedicine de Sevilla, in Spain, have
addressed this possibility in vitro and in vivo, in
three articles published in 2011. In the first study,
immunohistochemical analysis of 35 human lung
tumours at different stages and of different
histopathological grades showed that Spn protein is
absent in 20% and reduced in another 37% of
tumours, compared to normal lung tissue (MolinaPinelo et al., 2011). The loss of Spn expression
correlated with a less differentiated phenotype,
higher grade and poor prognosis. Lower or null
levels of Spn also correlated with nuclear
accumulation of p53, and so to mutated p53 or loss
of its wild-type activity. Moreover, loss of Spn
increased the tumourigenic properties of p53
deleted- or p53 mutated-lung tumour cells. The data
of this study showed that Spn down-regulation in
lung tumours contributes to carcinogenesis in the
absence of p53. There are several mechanisms that
might contribute to Spn down-regulation in
695
The tumour suppressor function of the scaffolding protein spinophilin
regulates the expression of p14 (ARF) (Liu et al.,
2012). Some members of the family of e2F
transcription factors are also involved in cell cycle
regulation; in particular E2F1 which expressions
increase induces augmentation of ARF which can
bind MDM2 and stabilize p53. In p53 (- / -) MEF,
reduced levels of Spn enhanced tumorigenic
potential of the cells. Indeed, inhibition of e2F by
Rb being lifted, this results in cell proliferation no
longer controlled by p53. Moreover, the absence of
Spn contributes to genetic alterations during MEF
immortalization, particularly p53 mutations. These
results extend the observations made by the authors
using a Spn-null mice model (Ferrer et al., 2011b).
In summary, the results suggested that Spn is a new
tumour suppressor acting via the regulation of pRb
and which function is revealed in the absence of a
functional p53 (Sarrouilhe and Ladeveze, 2012).
This is, therefore, suggestive of partially redundant
functions in their tumour suppression properties
(Santamaría and Malumbres, 2011). The results
also suggest that the specific outcome can be
context-dependent. Spn loss may be beneficial by
potentiating p53 in response to acute stress, and in
contrast it can be deleterious under sustained
mitogenic stress (Palmero, 2011). This feature is
reminiscent of NIAM (Nucleolar Interaction of
ARF and MDM2 protein) which acts through the
same partners p53 and ARF (Tompkins et al.,
2007).
Another Spn-interacting molecule is DCX, an actinbinding and microtubule-binding protein that seems
to be a tumour suppressor of glioma. When DCX is
ectopically expressed into the DCX-deficient U87
glioma cells, there is a marked suppression of the
transformed phenotype. The cells manifest a
reduced rate of growth in vitro and are arrested in
the G2 phase of the cell cycle. Moreover, DCXtransfected U87 glioma cells do not generate
tumours in immunocompromised nude rats. In
DCX-transfected U87 cells, phosphorylated DCX
binds specifically to Spn and this interaction
inhibits proliferation and anchorage-independent
growth in glioma cells. In contrast, DCX-mediated
growth repression is lost in glioma cells treated
with siRNA to Spn and in HEK 293 (human
embryonic kidney) Spn null cell line (Santra et al.,
2006). DCX, Spn and PP1c were found in the same
protein complex from mouse brain extracts
(Shmueli et al., 2006).
DCX-mediated growth arrest in glioma cells may
be through inactivation of PP1 activity by
Spn/DCX interaction in the cytosol. Inhibition of
PP1 activity is involved in two mechanistic links of
reduction
of
glioma
tumour-associated
progressions: firstly, catastrophe in mitotic
microtubule spindle that blocks mitosis; secondly,
depolymerization of actin that inhibits glioma cell
invasion (Santra et al., 2009).
tumours, including miRNAs overexpression.
miRNA106*, targeting Spn, are overexpressed in a
small subset of patients with decreased Spn levels.
Overexpression of miRNA106* significantly
increased the tumorigenic properties of lung tumour
cells. The results suggested that miRNA106*
overexpression found in a subset of lung tumours
might contribute to tumorigenesis through Spn
down-regulation in the absence of p53. In a second
study, tumour suppression by Spn was explored in
in vivo model using genetically modified mice
(Ferrer et al., 2011b). Spn-null (-/-) mice displayed
decreased survival, increased the number of
premalignant lesions in tissues such as the
mammary ducts and early appearance of
spontaneous tumours, such as lymphoma, when
compared to WT littermates. In another series of
experiments, the presence of mutant p53 activity
(p53R172H) in the mammary glands was evaluated
on a Spn heterozygous (+/-) or homozygous (-/-)
background in mice. An increased number of
premalignant lesions and of mammary carcinomas
were observed in Spn heterozygous (+/-) or
homozygous (-/-) mice when compared to WT
littermates. The results confirmed the functional
relationship between Spn and p53 in tumorigenicity
and showed that Spn loss contributes to tumour
progression rather than the tumour initiation. In a
third study using mouse embryonic fibroblasts
(MEFs), it was suggested that Spn acts as a tumour
suppressor by the regulation of the stability of
PP1cα, thereby regulating its activity on pRb (the
phosphorylated form of the Retinoblastoma
protein). This function of PP1cα has been
associated with the growth arrest response; the
hypophosphorylated form of Rb protein being the
most abundant when cells are delayed in their
growth (Ceulemans and Bollen, 2004). The ectopic
overexpression of Spn in immortalized MEF greatly
reduced tumour cell growth. Moreover, the absence
of Spn (Spn(-/-) MEF) down-regulated PP1α
activity resulting in a high level of pRb (Ferrer et
al., 2011a). High level of proproliferative
phosphorylated Rb leads to e2F activation, a
compensatory ARF transcription, and consequently
p53 activation. As they regulate the cell cycle, p53
and ARF are both tumour suppressors, which are
themselves regulated by MDM2 (Mouse double
minute 2) protein shuttle between the nucleus and
cytoplasm (Kamijo et al., 1998; Pomerantz et al.,
1998). Moreover, Sherr et al. (2005) suggested for
the first time a p53-independent pathway via the
ARF sumoylation. Ha et al. (2007) described ARF
as a melanoma tumour suppressor by inducing p53independent senescence. Moreover, Du et al. (2011)
demonstrated the functional roles of ERK and p21
for ARF in p53-independent tumour suppression.
Furthermore, in a p53-independent pathway, the
over-expression of wild-type c-myc obviously up-
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Sarrouilhe D, Ladeveze V
Figure 3. Cellular cycle regulation by spinophilin. A. In normal cells, the presence of nuclear p53 and Spn proteins regulates
cell cycle. The binding of PP1ca to Spn allows dephosphorylation of pRb, which inhibits E2F1 and thus the proliferation.
Furthermore both tumour suppressors (p53 and ARF) regulate the cell cycle. The nucleolar ARF is also a partner of Spn, and
regulates the cell cycle via Mdm2 and E2F1. B. In the case of colorectal carcinomas, Spn play a role in regulation of cell cycle
via a p53/ARF independent pathway. One hypothesis suggested by the team of Amancio Carnero is that the Ras/Raf pathway
could be implicated (Estevez-Garcia et al., 2013). This cytoplasmic pathway could be regulated by cytoplasmic Spn. K-Ras:
GTPase, oncogene; B-Raf: serine/threonine protein kinase, proto-oncogene; Mek: tyrosine/threonine kinase (Mapk kinase);
Mapk: mitogen-activated protein kinase.
diagnosed after the 10-year follow-up in 85.2%
cases with Spn low expression and 60.9% with Spn
high expression. Death occurred in 76.5% cases
with Spn low expression and in 56.5% cases with
Spn high expression. Overall, low Spn expression is
a factor for poor prognosis in hepatocellular
carcinoma. In vitro experiments (human hepatoma
cell line HepG2) and in vivo observations (Ki67positive tumour cells) showed that reduced Spn
expression significantly correlated with a higher
proliferation of liver cancer cells (Aigelsreiter et al.,
2013).
In the second study, the role of Spn was explored in
colorectal carcinoma, in which a number of
chromosomal regions are altered (Fearon, 2011).
Among them, the 17q21 is lost in a high percentage
of this carcinoma (Garcia-Patiño et al., 1998).
Quantitative RT-PCR analysis showed that
approximately 25% of colorectal carcinoma
tumours had a greater than 50% decrease in Spn
mRNA levels compared with normal colonic tissue.
A tissue array of human colorectal carcinomas was
generated to confirm this result by exploring the
presence of Spn protein. 70% of colorectal
carcinomas displayed high Spn levels (similar to
the values observed in normal tissue), 20% showed
intermediate levels and 10% showed no expression
of Spn. Moreover, Spn down-regulation correlated
with a more aggressive histologic phenotype
(higher Ki67-positive tumour cells) and was
associated with faster relapse and poorer survival in
patients with advanced stages of colorectal
carcinoma. The data also suggested that Spn loss
induced a chemoresistance in patients with
advanced stages of colorectal carcinoma that had
received adjuvant fluoropyrimidine chemotherapy
Moreover, double transfection with DCX and Spn
reduced self-renewal in brain tumour stem cells via
incomplete cell cycle endomitosis (Santra et al.,
2011). But, is there relevance for Spn as a
prognostic marker in patients with cancer? Spn is
absent in 20% and reduced in another 37% of
human lung tumors (Molina-Pinelo et al., 2011).
A further analysis of Spn in human tumours shows
that Spn mRNA is lost in a percentage of renal
carcinomas and lung adenocarcinomas. A clear
down-regulation of Spn was found in tumoral
samples of the CNS (oligodendrogliomas,
anaplastic astrocytomas, glioblastomas) when
compared to normal nervous samples. Furthermore,
lower levels of Spn mRNA correlate with higher
grade of ovarian carcinoma and chronic
myelogenous leukemia (Carnero, 2012). Two
articles published in spring 2013 associated Spn
loss with poor patient prognosis in patients with
carcinoma
(Sarrouilhe,
2014).
The
17q
chromosomal region is commonly impaired in
hepatocellular carcinoma (Furge et al., 2005). In the
first study, complete loss of Spn immunoreactivity
was found in 42.3% hepatocellular carcinoma and
reduced levels were found in additional 35.6%
cases. Quantitative RT-PCR analysis confirmed in
70% cases a significant reduced Spn mRNA
expression in tumour tissue compared with the
corresponding non-neoplastic tissue. miRNA106*,
targeting Spn in lung tumours, could not be
detected in any of the hepatocellular carcinoma
samples. Moreover, no correlations could be found
for the number of Spn-positive tumour cells and
p53 or ARF staining. These results suggested a
p53-independent tumorigenic role of Spn in
hepatocellular carcinoma. Disease recurrence was
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The tumour suppressor function of the scaffolding protein spinophilin
Sabatini DM, Snyder SH. Neurabin is a synaptic protein
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following surgical resection. Therefore, the
identification of the levels of Spn in advanced
stages of colorectal biopsies has prognostic and
predictive value and might contribute to select
patients who could or could not benefit from
current chemotherapy. In vitro and in vivo
experiments showed no functional relationship
between Spn levels and the presence or absence of
mutated p53 in colon cancer. The authors proposed
that this correlation is dependent on the molecular
context of the tumour cell (Estevez-Garcia et al.,
2013).
5- Discussion and perspectives
We are still only at the early stage in unravelling
the function of Spn in cell cycle regulation. Overall,
the different studies on the tumour suppressor
function of Spn show two pathways of cell cycle
regulation by Spn. The first model is a pathway
dependent of p53 and ARF.
This pathway was previously described in several
articles where Spn interacts with different partners
localized in the nucleus (Figure 3A). The second is
a pathway independent of both molecules. As Spn
is ubiquitously expressed in the cell, the first model
highlights the nuclear localization of Spn and its
interaction with other nuclear proteins.
The second model, more hypothetical, underlines
the possibility that Spn could interact with
cytoplasmic partners. The studies made on
colorectal carcinomas show that Spn could play a
role in a pathway independent of p53/ARF. One
hypothesis is that the Ras/Raf pathway and more
precisely K-Ras/B-Raf is implicated. This pathway,
via Mek (tyrosine/threonine kinase) and Mapk
(mitogen activated protein kinase) induces
transcription factors and proliferation survical
(Figure 3B).
Further studies are needed to elucidate the
underlying mechanisms linking Spn to carcinomas
and expand the prognostic and predictive value of
the Spn expression level to other types of cancer.
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700
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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OPEN ACCESS JOURNAL
Case Report Section
Paper co-edited with the European LeukemiaNet
Translocation t(5;6)(q33-34;q23) in an acute
myelomonocytic leukemia patient
Adriana Zamecnikova, Soad Al Bahar, Ramesh Pandita
Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait
(AZ, SA, RP)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Reports/t0506q33q23ZamecID100076.html
DOI: 10.4267/2042/54042
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Immunophenotype
Positive for CD13, CD15, CD117, CD33, MPO,
CD45, HLDR and dim CD34 (27%)
Diagnosis
Acute myelomonocytic leukemia
Abstract
Case report and literature review on translocation
t(5;6)(q33-34;q23) in an acute myelomonocytic
leukemia patient.
Clinics
Survival
Age and sex
68 years old female patient.
Previous history
No preleukemia, no previous malignancy, no inborn
condition of note, no main items.
Organomegaly
No hepatomegaly, no splenomegaly, no enlarged
lymph nodes, no central nervous system
involvement.
Date of diagnosis: 03-2013
Treatment: Chemotherapy (Daunorubicin &
Cytarabine combination therapy; consolidation with
high dose Ara-C)
Complete remission: no
Treatment related death: no
Relapse: yes
Phenotype at relapse: Acute myelomonocytic
leukemia
Status: Lost
Last follow up: 11-2013
Survival: 8 months
Blood
WBC: 104 X 109/l
HB: 7.8g/dl
Platelets: 57 X 109/l
Blasts: 84%
Bone marrow: Hypercellular marrow with 87%
blasts which were PAS diffuse granular positive
and SBB (Sudan Black B) positive.
Karyotype
Sample: Bone marrow, blood
Culture time: 24h
Banding: G-banding
Results
46,XX,t(5;6)(q33-34;q23)[25]
Karyotype at Relapse
46,XX,t(5;6)(q33-34;q23)[1]/46,XX,t(5;6)(q3334;q23),t(7;10)(p22;q23)[19]
Cyto-Pathology
Classification
Cytology
Acute myelomonocytic leukemia
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
701
Translocation t(5;6)(q33-34;q23) in an acute myelomonocytic leukemia patient
Zamecnikova A, et al.
Figure 1. A. Karyotype from the time of diagnosis showing the chromosomal translocation t(5;6)(q33-34;q23). B. Fluorescence in
situ hybridization studies (FISH) with XL 6q21/6q23 (Metasystem, Germany) probe showing red and green signals on both,
normal and der(6) chromosomes. C. Applying the XL PDGFR probe (Metasystem, Germany) showed normal signal pattern on
both normal and der(5) chromosomes, indicating that PDGFR located on 5q32-33 is not involved in the translocation. D.
Hybridization with whole chromosome 6 probe (Metasystem, Germany) showing translocation of chromosome 6 sequences to
der(5) chromosome.
ALL and an associated myeloproliferative
neoplasm and C6ORF204/PDGFRB fusion
(Chmielecki et al 2012).
While in this case, the chromosomal translocation
appeared to be morphologically identical to our
t(5;6)(q33-34;q23), in our patient PDGFRB (5q3233) is not rearranged and MYB (6q23)is not
translocated to chromosome 5 as in a previously
described case.
Due to the availability of tyrosine kinase inhibitors
for PDGFRB rearranged disorders, our findings
emphasize the importance of FISH in precise
characterizing of chromosome rearrangements with
5q33-34 breakpoints, especially in suboptimal
preparations.
Other molecular cytogenetics technics
Fluorescence in situ hybridization (FISH) with LSI
AML1-ETO, LSI MLL, LSI CBFB/inv(16), LSI
EGRI/5q31 (Abbott Molecular, Downers Grove,
IL) and XL 6q21/6q23, XL PDGFR, whole
chromosome 6 probe Metasystem, Germany).
Other molecular cytogenetics results
Normal signal patterns for LSI AML1-ETO, LSI
MLL, LSI CBFB/inv(16), LSI EGRI/5q31, XL
6q21/6q23 and XL PDGFR probes.
Comments
Chromosomal translocations involving 5q33 and
6q23 have been reported in only one patient with T-
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
702
Translocation t(5;6)(q33-34;q23) in an acute myelomonocytic leukemia patient
Zamecnikova A, et al.
Figure 2. A. Karyotype from blood cell from the time of relapse showing the t(5;6)(q33-34;q23) and a new anomaly
t(7;10)(p22;q23). B. Partial karyotypes from blood and bone marrow showing the t(5;6)(q33-34;q23).
Chromosomes Cancer. 2012 Jan;51(1):54-65
References
This article should be referenced as such:
Chmielecki J, Peifer M, Viale A, Hutchinson K, Giltnane J,
Socci ND, Hollis CJ, Dean RS, Yenamandra A, Jagasia M,
Kim AS, Davé UP, Thomas RK, Pao W. Systematic screen
for tyrosine kinase rearrangements identifies a novel
C6orf204-PDGFRB fusion in a patient with recurrent T-ALL
and an associated myeloproliferative neoplasm. Genes
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
Zamecnikova A, Al Bahar S, Pandita R. Translocation
t(5;6)(q33-34;q23) in an acute myelomonocytic leukemia
patient. Atlas Genet Cytogenet Oncol Haematol. 2014;
18(9):701-703.
703
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
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Translocation t(5;6)(q33-34;q23) in an acute myelomonocytic leukemia patient
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(9)
705
Zamecnikova A, et al.