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Volume 16 - Number 1
January 2012
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and
educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
Staff
Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le Berre,
Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year
by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French
National Center for Scientific Research (INIST-CNRS) since 2008.
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http://AtlasGeneticsOncology.org
© 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
OPEN ACCESS JOURNAL AT INIST-CNRS
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
Fei Chen
Antonio Cuneo
Paola Dal Cin
Louis Dallaire
Brigitte Debuire
François Desangles
Enric Domingo-Villanueva
Ayse Erson
Richard Gatti
Ad Geurts van Kessel
Oskar Haas
Anne Hagemeijer
Nyla Heerema
Jim Heighway
Sakari Knuutila
Lidia Larizza
Lisa Lee-Jones
Edmond Ma
Roderick McLeod
Cristina Mecucci
Yasmin Mehraein
Fredrik Mertens
Konstantin Miller
Felix Mitelman
Hossain Mossafa
Stefan Nagel
Florence Pedeutour
Elizabeth Petty
Susana Raimondi
Mariano Rocchi
Alain Sarasin
Albert Schinzel
Clelia Storlazzi
Sabine Strehl
Nancy Uhrhammer
Dan Van Dyke
Roberta Vanni
Franck Viguié
José Luis Vizmanos
Thomas Wan
(Ankara, Turkey)
(Milan, Italy)
(Rotterdam, The Netherlands)
(Leiden, The Netherlands)
(London, UK)
(Groningen, The Netherlands)
(Marseille, France)
(Morgantown, West Virginia)
(Ferrara, Italy)
(Boston, Massachussetts)
(Montreal, Canada)
(Villejuif, France)
(Paris, France)
(London, UK)
(Ankara, Turkey)
(Los Angeles, California)
(Nijmegen, The Netherlands)
(Vienna, Austria)
(Leuven, Belgium)
(Colombus, Ohio)
(Liverpool, UK)
(Helsinki, Finland)
(Milano, Italy)
(Newcastle, UK)
(Hong Kong, China)
(Braunschweig, Germany)
(Perugia, Italy)
(Homburg, Germany)
(Lund, Sweden)
(Hannover, Germany)
(Lund, Sweden)
(Cergy Pontoise, France)
(Braunschweig, Germany)
(Nice, France)
(Ann Harbor, Michigan)
(Memphis, Tennesse)
(Bari, Italy)
(Villejuif, France)
(Schwerzenbach, Switzerland)
(Bari, Italy)
(Vienna, Austria)
(Clermont Ferrand, France)
(Rochester, Minnesota)
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(Paris, France)
(Pamplona, Spain)
(Hong Kong, China)
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Solid Tumours Section
Genes Section
Genes / Leukaemia Sections
Solid Tumours Section
Leukaemia Section
Deep Insights Section
Solid Tumours Section
Genes / Deep Insights Sections
Leukaemia Section
Genes / Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia / Solid Tumours Sections
Solid Tumours Section
Solid Tumours Section
Cancer-Prone Diseases / Deep Insights Sections
Cancer-Prone Diseases Section
Genes / Leukaemia Sections
Deep Insights Section
Leukaemia Section
Genes / Deep Insights Sections
Deep Insights Section
Solid Tumours Section
Solid Tumours Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Leukaemia Sections
Cancer-Prone Diseases Section
Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Solid Tumours Sections
Deep Insights Section
Genes / Leukaemia Section
Genes Section
Cancer-Prone Diseases Section
Education Section
Genes Section
Genes / Leukaemia Sections
Genes / Cancer-Prone Diseases Sections
Education Section
Solid Tumours Section
Leukaemia Section
Leukaemia Section
Genes / Leukaemia Sections
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 16, Number 1, January 2012
Table of contents
Gene Section
ADAM10 (ADAM metallopeptidase domain 10)
Pascal Gelebart, Hanan Armanious, Raymond Lai
1
BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))
Victor M Bolanos-Garcia, Tom L Blundell
7
FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)
Mark Pickard
12
GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))
Stephanie Schulz, Scott A Waldman
18
LIN28B (lin-28 homolog B (C. elegans))
Yung-Ming Jeng
20
PKD1 (polycystic kidney disease 1 (autosomal dominant))
Ying-Cai Tan, Hanna Rennert
22
AMFR (autocrine motility factor receptor)
Yalcin Erzurumlu, Petek Ballar
25
ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila))
Paul F South, Scott D Briggs
30
CD109 (CD109 molecule)
Shinji Mii, Yoshiki Murakumo, Masahide Takahashi
34
CLDN7 (claudin 7)
Ana Carolina de Carvalho, Andre Vettore
37
CSE1L (CSE1 chromosome segregation 1-like (yeast))
Ming-Chung Jiang
41
DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5)
Zhi-Ren Liu
44
Leukaemia Section
t(13;19)(q14;p13)
Jean-Loup Huret
48
t(17;17)(q21;q24), del(17)(q21q24)
Jean-Loup Huret
49
Deep Insight Section
MicroRNAs and Cancer
Federica Calore, Muller Fabbri
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
51
t(11;14)(q13;q32)
in multiple myeloma
Atlas
of Genetics
and Cytogenetics
in Oncology and Haematology
Huret JL, Laï JL
OPEN ACCESS JOURNAL AT INIST-CNRS
Case Report Section
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Francesca Cambosu, Giuseppina Fogu, Paola Maria Campus, Claudio Fozza, Luigi Podda,
Andrea Montella, Maurizio Longinotti
70
Educational Items Section
Weird animal genomes and sex chromosome evolution
Jenny Graves
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
73
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
ADAM10 (ADAM metallopeptidase domain 10)
Pascal Gelebart, Hanan Armanious, Raymond Lai
Department of Laboratory Medicine and Pathology, University of Alberta, Room 1466, 11560 University
Avenue, T6G 1Z2-Edmonton, Alberta, Canada (PG, HA, RL)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAM10ID44397ch15q21.html
DOI: 10.4267/2042/47258
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
part is divided into 16 exons.
Other names: AD10, CD156c, HsT18717, MADM,
kuz
HGNC (Hugo): ADAM10
Location: 15q21.3
Only one type of transcript has been described. The
2247-nucleotide transcript encodes a protein of 748
amino acid residues. The first and last exons are
partially untranslated.
Transcription
Pseudogene
DNA/RNA
None described so far.
Description
The gene spans a region of 15.36 kb and the coding
Figure 1. Representation of the ADAM10 gene organization.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
1
ADAM10 (ADAM metallopeptidase domain 10)
Gelebart P, et al.
Two proteins, the convertase 7 and the furin, have been
implicated in the activation of ADAM10 (Anders et al.,
2001). To date the major function of ADAM10 appears
to be attributed to its enzymatic activity as a
metalloproteinase. In fact, ADAM10 is involved in the
intra-membrane proteolysis process, whereby it
mediates ectodomain shedding of various membrane
bound receptors, adhesion molecules, growth factors
and cytokines like TNF-alpha (Rosendahl et al., 1997;
Lunn et al., 1997; Hikita et al., 2009; Mezyk-Kopec et
al., 2009), Notch (Hartmann et al., 2002; Gibb et al.,
2010), E-cadherin (Maretzky et al., 2005), Ephrin
(Janes et al., 2005), HER-2 (Liu et al., 2006), CD30
(Eichenauer et al., 2007), CD44 (Anderegg et al., 2009)
and IL-6 receptor to name a few. The functional role of
the SH3 domains of ADAM10 has never been studied.
Moreover, the recent observation that ADAM10 can be
found in the nucleus of some cells raises the possibility
of new and uncovers function of ADAM10 (Arima et
al., 2007).
ADAM10 seems to be detrimental for embryogenesis
as the knockout mice for ADAM10 die at day 9.5 of
embryogenesis (Hartmann et al., 2002). The mice
present several developmental defects in the nervous
central system as well in the cardiovascular system.
This latest observation correlates well with the fact that
ADAM10 transcript is highly expressed in
cardiomyocyte.
In human, ADAM10 was recently been demonstrated
to be a regulator of the lymphocyte development (Gibb
et al., 2011).
Protein
Description
ADAM10 is a metalloproteinase composed of 748
residues.
Expression
ADAM10 RNA has been reported to be present in wide
range of human tissue (Yanai et al., 2005). Data
obtained from GeneAtlas have shown that ADAM10
transcript is the most highly expressed in myeloid, NK
cells and monocytes as well as cardiomyocytes and
smooth muscle cells (figure 3). At the protein level,
ADAM10 has been reported in epithelials tissue of the
heart, liver and kidney (Hall and Erickson, 2003).
Localisation
ADAM10 is localized at the plasma membrane.
However, nuclear localization of ADAM10 has been
reported in prostate cancer and in mantle cell
lymphoma cells (Armanious et al., 2011).
Function
ADAM10 belongs to the family of metalloproteinases
(Chantry et al., 1989; Chantry and Glynn, 1990;
Edwards et al., 2008). ADAM10 protein is composed
of multiple functional domains that include: a
prodomain, a catalytic domain, a cysteine-rich domain,
a transmembraneous domain, a cytoplasmic domain
and a SH3 domain (Seals and Courtneidge, 2003;
Edwards et al., 2008) (see figure 4). ADAM10 is
synthesized as a pro-protein and therefore needs to be
cleaved to be activated (Anders et al., 2001).
Figure 2. Crystal structure of ADAM10 Disintegrin and cysteine-rich domain at 2.9 A resolution. Adapted from PDB (access
number: 2AO7).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
2
ADAM10 (ADAM metallopeptidase domain 10)
Gelebart P, et al.
Figure 3. ADAM10 tissue expression profile. Adapted from GeneAtlas U113A.
Figure 4. ADAM10 protein structure organization.
Brain tumors
Mutations
Note
ADAM10 protein has been reported to be highly
expressed in the human central nervous system
(Kärkkäinen et al., 2000). Recently, two different
studies (Kohutek et al., 2009; Formolo et al., 2011)
have uncovered the function of ADAM10 in the cell
migration and invasiveness process of glioblastoma
cells. In fact the authors have shown that ADAM10 by
mediating the cleavage of N-cadherin was found to
regulate the migratory properties of glioblastoma cells
(Kohutek et al., 2009). On the other hand, the protein
expression of ADAM10 was found to be higher in cell
with strong invasiveness capability.
Note
No mutation has been reported so far.
Implicated in
Various cancers
Note
ADAM family members have been recently involved in
malignant progression and development (Mochizuki
and Okada, 2007; Rocks et al., 2008; Wagstaff et al.,
2011; Duffy et al., 2009). ADAM10 has been shown to
be constitutively active in a number of solid tumors,
and this biochemical defect is implicated in the
pathogenesis of many tumors. The following
paragraphs will summarize what has been discovered
about the function of ADAM10 in cancer.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Prostate cancer
Note
Prostate cancer is one of the most frequent cancers in
men. The cause of prostate cancer development is
3
ADAM10 (ADAM metallopeptidase domain 10)
Gelebart P, et al.
unknown but is likely to be arising from several factors.
Development of prostate cancer is androgen-dependent
in early stages of the disease but cell growth became
androgen-independent. ADAM10 have been found to
be expressed in all prostate tumor samples (Karan et
al., 2003). Interestingly, McCulloch et al. have
observed that ADAM10 expression was up-regulated
by androgen stimulation. Those observations were
confirmed in a study published by Arima et al.
However, in this work they reveal that ADAM10 was
predominantly localized in the nucleus of cancer cells
and show that ADAM10 can co-immunoprecipitate
with androgen receptor in the nucleus. Moreover, they
also observed that nuclear expression of ADAM10 was
correlating with several biological parameters like the
Gleason score and prostate specific antigen expression.
Inhibition of ADAM10 expression by a siRNA
approach was able to induce a cell proliferation
decrease of prostate cancer cells. This study suggests
for the first time that ADAM10 may have some
function in the nucleus by regulating androgen receptor
function.
outcome
(Wang
et
al.,
2011).
Using
immunohistochemistry, it was also found that
ADAM10 is over-expressed in squamous cell
carcinomas of the oral cavity, as compared to the
benign epithelial cells; knockdown of ADAM10
expression using siRNA in the cell lines derived from
those tumors induces a significant decrease in cell
growth (Ko et al., 2007).
Melanoma, pancreatic cancer and
adenoid cystic carcinoma
Note
The expression of ADAM10 has been investigated in
melanoma and Lee et al. have reported that ADAM10
is over-expressed in melanoma metastasis in
comparison to primary melanoma cells. Similar
findings were made in pancreatic cancer, where
inhibition of ADAM10 expression in pancreatic
carcinoma cell lines also resulted in a significant
decrease in invasiveness and migration (Gaida et al.,
2010).
Hematologic malignancies
Breast cancer
Note
Recently, Armanious et al. have described for the first
time the function of ADAM10 in non solid tumors.
They have reported that ADAM10 is constitutively
activated and over-expressed in different form of B-cell
lymphoma like mantle cell lymphoma and diffuse large
B-cell lymphoma. Moreover, the authors have
described that inhibition of ADAM10 leads to a
decrease of cell proliferation. On the other hand,
stimulation of mantle cells with the recombinant active
form of ADAM10 increases further their proliferation.
Additionally, they also demonstrated, as reported
previously in the literature, that ADAM10 was
responsible for the release of active from of TNF-alpha
that in turn was contributing to the activation of the
NF-kappab pathways.
Note
Expressions of different members of the ADAM family
have been investigated in breast cancer. Despite that
some ADAM family members present differential
expression between non neoplastic and breast cancer
tissue, no difference was observed for ADAM10
(Lendeckel et al., 2005). Nevertheless, Liu and coworkers have recently described than ADAM10 was
the principal responsible for HER2 shedding in HER2
over-expressing breast cancer. The cleavage of HER2
liberates the extracellular domain of HER2 leaving a
p95 fragment containing the transmembrane domain as
well as the intracellular domain. This p95 fragment
presents constitutive kinase activation and its
expression correlates with a poor prognosis. The author
demonstrated that in conjunction with low amount of
HER2 inhibitor, ADAM10 inhibition was inducing a
decrease in cell proliferation.
To be noted
Note
To summarize, the function of ADAM protein family
members emerge as an important player in the
pathobiology of various form of cancers. Therefore,
they represent today a new therapeutic target of choice
for cancer therapy. In particular, ADAM10 is the object
of intense drug development (Soundararajan et al.,
2009; Crawford et al., 2009; Yavari et al., 1998; Moss
et al., 2008).
Colon and gastric and oral carcinomas
Note
Deregulation of ADAM10 in colon cancer development
has been reported in several studies. Knösel et al. have
reported that ADAM10 expression in colorectal cancer
patient samples, detectable by immunohistochemistry
was found to correlate with higher clinical stage.
Moreover, it has been demonstrated that xenografting
of colorectal cancer cells with enforced expression of
ADAM10 in nude mice induced formation of liver
metastasis compared to the negative control cells, and
this effect can be attributed to ADAM10-mediated
cleavage and release of L1-CAM, a cell adhesion
molecule (Gavert et al., 2007). Similarly to Knösel et
al., ADAM10 expression was associated with gastric
cancer progression and correlates with worst prognostic
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Yanai I, Benjamin H, Shmoish M, Chalifa-Caspi V, Shklar M,
Ophir R, Bar-Even A, Horn-Saban S, Safran M, Domany E,
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
5
ADAM10 (ADAM metallopeptidase domain 10)
Gelebart P, et al.
Kohutek ZA, diPierro CG, Redpath GT, Hussaini IM. ADAM10-mediated N-cadherin cleavage is protein kinase C-alpha
dependent and promotes glioblastoma cell migration. J
Neurosci. 2009 Apr 8;29(14):4605-15
upregulated in melanoma metastasis compared with primary
melanoma. J Invest Dermatol. 2010 Mar;130(3):763-73
Xu Q, Liu X, Chen W, Zhang Z. Inhibiting adenoid cystic
carcinoma cells growth and metastasis by blocking the
expression of ADAM 10 using RNA interference. J Transl Med.
2010 Dec 20;8:136
Mezyk-Kopeć R, Bzowska M, Stalińska K, Chełmicki T,
Podkalicki M, Jucha J, Kowalczyk K, Mak P, Bereta J.
Identification of ADAM10 as a major TNF sheddase in
ADAM17-deficient fibroblasts. Cytokine. 2009 Jun;46(3):30915
Armanious H, Gelebart P, Anand M, Belch A, Lai R.
Constitutive activation of metalloproteinase ADAM10 in mantle
cell lymphoma promotes cell growth and activates the
TNFα/NFκB pathway. Blood. 2011 Jun 9;117(23):6237-46
Soundararajan R, Sayat R, Robertson GS, Marignani PA.
Triptolide: An inhibitor of a disintegrin and metalloproteinase 10
(ADAM10) in cancer cells. Cancer Biol Ther. 2009
Nov;8(21):2054-62
Formolo CA, Williams R, Gordish-Dressman H, MacDonald TJ,
Lee NH, Hathout Y. Secretome signature of invasive
glioblastoma multiforme. J Proteome Res. 2011 Jul
1;10(7):3149-59
Gaida MM, Haag N, Günther F, Tschaharganeh DF,
Schirmacher P, Friess H, Giese NA, Schmidt J, Wente MN.
Expression of A disintegrin and metalloprotease 10 in
pancreatic carcinoma. Int J Mol Med. 2010 Aug;26(2):281-8
Gibb DR, Saleem SJ, Chaimowitz NS, Mathews J, Conrad DH.
The emergence of ADAM10 as a regulator of lymphocyte
development and autoimmunity. Mol Immunol. 2011
Jun;48(11):1319-27
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J, Yagita H, Tew JG, Dempsey PJ, Crawford HC, Conrad DH.
ADAM10 is essential for Notch2-dependent marginal zone B
cell development and CD23 cleavage in vivo. J Exp Med. 2010
Mar 15;207(3):623-35
Wagstaff L, Kelwick R, Decock J, Edwards DR. The roles of
ADAMTS metalloproteinases in tumorigenesis and metastasis.
Front Biosci. 2011 Jan 1;16:1861-72
Wang YY, Ye ZY, Li L, Zhao ZS, Shao QS, Tao HQ. ADAM 10
is associated with gastric cancer progression and prognosis of
patients. J Surg Oncol. 2011 Feb;103(2):116-23
Gutwein P, Schramme A, Abdel-Bakky MS, Doberstein K,
Hauser IA, Ludwig A, Altevogt P, Gauer S, Hillmann A, Weide
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Jan 13;17:3
This article should be referenced as such:
Gelebart P, Armanious H, Lai R. ADAM10 (ADAM
metallopeptidase domain 10). Atlas Genet Cytogenet Oncol
Haematol. 2012; 16(1):1-6.
Lee SB, Schramme A, Doberstein K, Dummer R, Abdel-Bakky
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Pfeilschifter J, Mihic-Probst D, Gutwein P. ADAM10 is
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
6
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
BUB1 (budding uninhibited by benzimidazoles 1
homolog (yeast))
Victor M Bolanos-Garcia, Tom L Blundell
Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK (VMBG, TLB)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/BUB1ID853ch2q13.html
DOI: 10.4267/2042/47259
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Amino acid sequence (FASTA format).
Identity
Description
Other names: BUB1A, BUB1L, hBUB1
HGNC (Hugo): BUB1
Location: 2q13
Note
The multidomain protein kinase BUB1 is a central
component of the mitotic checkpoint for spindle
assembly (SAC). This evolutionary conserved and
essential self-monitoring system of the eukaryotic cell
cycle ensures the high fidelity of chromosome
segregation by delaying the onset of anaphase until all
chromosomes are properly bi-oriented on the
microtubule spindle.
1085 amino acids, 122.37 kDa.
Expression
Ubiquituously expressed.
Localisation
Cytoplasmic in interphase cells. It is localized in
nuclear kinetochores in cells with an unsatisfied mitotic
checkpoint in a process that requires BUB1 binding to
Blinkin and BUB3.
Function
BUB1 is required for chromosome congression,
kinetochore localization of BUBR1, CENP-E, CENP-F
and Mad2 in cells with mitotic checkpoint unsatisfied
and for the establishment and/or maintenance of
efficient bipolar attachment to spindle microtubules
(Johnson et al., 2004; Lampson and Kapoor, 2005;
McGuinness et al., 2009). Deletion of Bub1 from S.
pombe increases the rate of chromosome
missegregation (Bernard et al., 1998) while deletion of
Bub1 from S. cerevisiae results in slow growth and
elevated chromosome loss (Warren et al., 2002).
BUB1 is recruited very early in prophase (Wong and
Fang, 2006) and is essential for assembly of the
functional inner centromere (Taylor et al., 1998;
Boyarchuk et al., 2007).
DNA/RNA
Description
The gene spans 40.2 kb and is composed of 25 exons.
Transcription
NM_004336.3
Protein
Note
Uniprot accession number: NP_004327.1.
ENZYME entry (serine/threonine protein kinase): EC
2.7.11.1.
Figure 1. Schematic representation of the human bub1 gene demonstrating the relative size of each of the 25 exons (introns are not
drawn to scale).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
7
BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))
Bolanos-Garcia VM, Blundell TL
Figure 2. Domain organization of BUB1. Three main regions can be identified in the BUB1 gene product: a conserved N-terminal region,
which contains the kinetochore localization domain; an intermediate, non-conserved region, which is required for Bub3 binding; and a Cterminal region containing a catalytic serine/threonine kinase domain. The main functions associated with the different BUB1 regions are
also indicated.
It accumulates at the kinetochore in SAC-activated
cells and assures the correct kinetochore formation.
The N-terminal region mediates the binding of BUB1
to the mitotic kinetochore protein Blinkin (a protein
also
commonly
referred
to
as
KNL1/Spc105/AF15q14); the interaction is essential
for the kinetochore localization of BUB1 induced in
cells with an unsatisfied mitotic checkpoint (Kiyomitsu
et al., 2007). N-terminal BUB1 is organised as a triple
tandem of the TPR motif (Bolanos-Garcia et al., 2009).
In fission yeast, the Bub1 N-terminal residues 1-179
are required for targeting the protein Shugoshin 1
(SGO1) to centromeres (Vaur et al., 2005) while
deletion of residues 28-160 results in a truncated
protein unable to recruit Bub3 and Mad3/BUB1B to
kinetochores (Vanoosthuyse et al., 2004). The Cterminal region contains a catalytic, serine threonine
kinase domain that resembles the mechanism of
activation of CDKs by cyclins (Kang et al., 2008).
mouse, rat, chicken, and zebrafish. Homology exists
with the gene encoding for the mitotic checkpoint
kinase BUBR1 (a BUB1 paralogue) (Bolanos-Garcia
and Blundell, 2011).
Mutations
The following somatic mutations have been reported to
date: A130->S (Shichiri et al., 2002); deletion delta76141 (Cahill et al., 1998); 140, transition of the splicing
donor site (Cahill et al., 1998); S492->Y (Cahill et al.,
1998); deletion delta827 (Ouyang et al., 2002); G250>N (Ohshima et al., 2000); S950->G (Imai et al.,
1999); Y259->C (Hempen et al., 2003); H265->N
(Hempen et al., 2003). It could not be determined
whether the R209->Q substitution was the result of a
somatic mutation or due to a rare polymorphism
because constitutional DNA from the patient
harbouring this mutation was not available (Sato et al.,
2000). The clinical condition associated to each
mutation is described in Table 1. The mapping of
residues substitutions onto the BUB1 domains is
depicted in Figure 3.
Homology
The bub1 gene is conserved in chimpanzee, cow,
Bub1 region
Mutation
Residue
Domain
GAG→GAT E36→D
N-terminal
Colorectal cancer
Cahill et al., 1999
∆76-141,
frameshift
Colorectal cancer
Cahill et al., 1998
GCT→TCT
A130→S
Lymph node metastasis
Shichiri et al., 2002
G→A
140, transition
of the splicing
donor site
Colorectal cancer
Cahill et al., 1998
Lung cancer
Sato et al., 2000
ATLL
Ohshima et al., 2000*
GGT→GAT
G250→N
TAT→TGT
Y259→C
Pancreatic cancer
Hempen et al., 2003
CAC→AAC
H265→N
Pancreatic cancer
Hempen et al., 2003
S375→F
Colorectal cancer
Saeki et al., 2002
S492→Y
Colorectal cancer
Cahill et al., 1998
K566→R
Colorectal cancer
Saeki et al., 2002
P648→R
Colorectal cancer
Cahill et al., 1999
∆827,
frameshift
Tyroid follicular adenoma
Ouyang et al., 2002
Colorectal cancer
Imai et al., 1999
TCC→TTC
Middle region
of
low TCT→TAT
structural
AAG→AGG
complexity
CCC→CGC
Deletion
C-terminal
Reference
Deletion
CGA→CAA R209→Q
GLEBS motif
Clinical condition
S950→G
TPR domain
Kinase
domain
Table 1. Human bub1 mutations associated with cancer. *These authors incorrectly number these residues; the numbering shown here
is the correct.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
8
BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))
Bolanos-Garcia VM, Blundell TL
Figure 3. Mapping of cancer associated substitutions onto the amino acid sequence of human BUB1.
phenylalanine (TTC) at codon 375 while the other has a
lysine (AAG) substituted for arginine (AGG) at codon
566 (Saeki et al., 2002). S375F showed a welldifferentiated HCC in cirrhotic liver caused by hepatitis
B virus, whereas K566R showed a moderately
differentiated HCC in hepatitis C virus induced
cirrhotic liver. Genomic DNA extracted from
nontumorous liver tissue revealed the same variants in
both cases.
Implicated in
Colorectal cancer
Disease
Colorectal cancer, also referred to as bowel cancer, is
characterized by neoplasia in the colon, rectum, or
vermiform appendix. Colorectal cancer is the third
most commonly diagnosed cancer in the world and
fourth most frequent cause of cancer death in males.
More than half of the people who die of colorectal
cancer live in a developed region of the world.
Cytogenetics
RT-PCR mediated amplification and direct sequencing
of the entire BUB1 coding region in the colorectal
cancer cell line V400 revealed an internal deletion of
197 bp of this gene (Cahill et al., 1998). The deletion
results in the remotion of codons 76 to 141 and creates
a frameshift immediately thereafter. Sequence analysis
of cDNA from another colorectal cancer cell line,
V429, revealed a missense mutation at codon 492 that
resulted in the substitution of tyrosine for a conserved
serine (Cahill et al., 1998). The V400 and V429
mutations were heterozygous, somatic and present in
primary tumours but not in normal tissues. Another
heterozygous BUB1 missense mutation (AGT to GGT)
at codon 950 has been identified (Imai et al., 1999).
Lung cancer
Disease
Lung cancer is the most frequently diagnosed cancer
among men. The mortality rate is the highest among
men and the second highest among women worldwide.
The main types of lung cancer are small-cell lung
carcinoma and non-small-cell lung carcinoma. Nonsmall-cell lung carcinoma is sometimes treated with
surgery, while small-cell lung carcinoma usually
responds better to chemotherapy and radiation. Lung
cancer cells harbour many cytogenetic abnormalities
suggestive of allele loss, including non-reciprocal
translocations and aneuploidy. The stage of the disease
is a strong predictor of survival, suggesting that early
detection is needed for improvement in treatment
outcomes.
Cytogenetics
A nucleotide change of the BUB1 gene that results in
the substitution of Arginine by Glutamine R209Q has
been identified in the cell line NCI-H345 (Sato et al.,
2000). Unfortunately, it was not possible to determine
whether the change was a somatic mutation or a rare
polymorphism because constitutional DNA from this
patient was not available.
Hepatocellular carcinoma (HCC)
Disease
Hepatocellular carcinoma (HCC) is one of the most
common tumors worldwide and it accounts for most
liver cancers. HCC occurs more often in men than
women and is more common in people ages 30-50.
Hepatitis virus infection, alcohol consumption, and
dietary exposure to toxins such as aflatoxin B1 are
associated with the occurrence of HCC.
Cytogenetics
Two BUB1 gene variants have been identified in HCC
specimens (Saeki et al., 2002). The expression product
of one variant has a serine (TCC) substituted for
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Adult T-cell leukaemia/lymphoma
(ATLL)
Disease
Lymphomas, malignancies of the lymphoid cells, are
divided on the basis of their pathologic features into
Hodgkin lymphoma (HL) and non-Hodgkin lymphoma
9
BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))
(NHL). Adult T-cell leukemia/lymphoma (ATLL) is
usually a highly aggressive non-Hodgkin's lymphoma
of the patient's own T-cells with no characteristic
histologic appearance except for a diffuse pattern and a
mature T-cell phenotype. The frequent isolation of
HTLV-1 from patients with this disease and the
detection of HTLV-1 proviral genome in ATLL
leukemic cells suggest that HTLV-1 causes ATLL.
Cytogenetics
A BUB1 missense mutation of G to A at codon 250
(GGT to GAT) has been reported (Ohshima et al.,
2000).
Lymph node metastasis
Disease
Certain cancers spread in a predictable fashion from
where the cancer started. Because the flow of lymph is
directional, if the cancer spreads it will spread first to
lymph nodes close to the tumor before it spreads to
other parts of the body.
Cytogenetics
A BUB1 missense somatic mutation (nucleotide 437
GCT to TCT transition) that replaces Ala to Ser at
codon 130 has been identified in an ascending
colorectal carcinoma (Shichiri et al., 2002).
Pancreatic cancer
References
Disease
The term pancreatic cancer usually refers to
adenocarcinoma that arises within the exocrine
component of the pancreas. Pancreatic cancer is one of
the most aggressive diseases with most cancers and
often has a poor prognosis: for all stages combined, the
1- and 5-year relative survival rates are 25% and 6%,
respectively; for local disease the 5-year survival is
approximately 20% while the median survival for
locally advanced and for metastatic disease, which
collectively represent over 80% of individuals, is about
10 and 6 months respectively.
Cytogenetics
Two missense variants in the BUB1 gene have been
identified in the aneuploid pancreatic cell line Hs766T
(Hempen et al., 2003). These mutations are found in the
same allele, accompanied by a wild-type BUB1 allele.
Mutation of nucleotide 776 from an adenine to a
guanine results in an amino acid change at codon 259
from tyrosine to cysteine (Y259C). A second mutation
at nucleotide 793 changed a cytosine to an adenine (C
to A) thus resulting in the mutant H265N (Hempen et
al., 2003).
Taylor SS, McKeon F. Kinetochore localization of murine Bub1
is required for normal mitotic timing and checkpoint response
to spindle damage. Cell. 1997 May 30;89(5):727-35
Bernard P, Hardwick K, Javerzat JP. Fission yeast bub1 is a
mitotic centromere protein essential for the spindle checkpoint
and the preservation of correct ploidy through mitosis. J Cell
Biol. 1998 Dec 28;143(7):1775-87
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK,
Markowitz SD, Kinzler KW, Vogelstein B. Mutations of mitotic
checkpoint genes in human cancers. Nature. 1998 Mar
19;392(6673):300-3
Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW,
Vogelstein B, Lengauer C. Characterization of MAD2B and
other mitotic spindle checkpoint genes. Genomics. 1999 Jun
1;58(2):181-7
Imai Y, Shiratori Y, Kato N, Inoue T, Omata M. Mutational
inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1,
is rare in sporadic digestive tract cancers. Jpn J Cancer Res.
1999 Aug;90(8):837-40
Ohshima K, Haraoka S, Yoshioka S, Hamasaki M, Fujiki T,
Suzumiya J, Kawasaki C, Kanda M, Kikuchi M. Mutation
analysis of mitotic checkpoint genes (hBUB1 and hBUBR1)
and microsatellite instability in adult T-cell leukemia/lymphoma.
Cancer Lett. 2000 Oct 1;158(2):141-50
Thyroid follicular adenoma
Sato M, Sekido Y, Horio Y, Takahashi M, Saito H, Minna JD,
Shimokata K, Hasegawa Y. Infrequent mutation of the hBUB1
and hBUBR1 genes in human lung cancer. Jpn J Cancer Res.
2000 May;91(5):504-9
Disease
Almost all thyroid adenomas are follicular adenomas.
Follicular adenomas can be described as "cold",
"warm" or "hot" depending on their level of function.
Histopathologically, follicular adenomas can be
classified according to their cellular architecture and
relative amounts of cellularity and colloid into the
following types:
- fetal (microfollicular), which have the potential for
microinvasion,
- colloid (macrofollicular), which do not have any
potential for microinvasion,
- embryonal (atypical), which have the potential for
microinvasion.
Cytogenetics
A thyroid follicular carcinoma that has a 2-bp somatic
deletion (G2480/A2481) of BUB1 has been reported by
Ouyang and collaborators (2002).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Bolanos-Garcia VM, Blundell TL
Ouyang B, Knauf JA, Ain K, Nacev B, Fagin JA. Mechanisms
of aneuploidy in thyroid cancer cell lines and tissues: evidence
for mitotic checkpoint dysfunction without mutations in BUB1
and BUBR1. Clin Endocrinol (Oxf). 2002 Mar;56(3):341-50
Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I,
Kawata S, Matsuzawa Y. Frequent impairment of the spindle
assembly checkpoint in hepatocellular carcinoma. Cancer.
2002 Apr 1;94(7):2047-54
Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y.
Genetic and epigenetic inactivation of mitotic checkpoint genes
hBUB1 and hBUBR1 and their relationship to survival. Cancer
Res. 2002 Jan 1;62(1):13-7
Warren CD, Brady DM, Johnston RC, Hanna JS, Hardwick KG,
Spencer FA. Distinct chromosome segregation roles for
spindle checkpoint proteins. Mol Biol Cell. 2002
Sep;13(9):3029-41
Hempen PM, Kurpad H, Calhoun ES, Abraham S, Kern SE. A
double missense variation of the BUB1 gene and a defective
10
BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast))
Bolanos-Garcia VM, Blundell TL
mitotic spindle checkpoint in the pancreatic cancer cell line
Hs766T. Hum Mutat. 2003 Apr;21(4):445
through direct interaction with Bub1 and BubR1. Dev Cell.
2007 Nov;13(5):663-76
Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is
required for kinetochore localization of BubR1, Cenp-E, CenpF and Mad2, and chromosome congression. J Cell Sci. 2004
Mar 15;117(Pt 8):1577-89
Wong OK, Fang G. Cdk1 phosphorylation of BubR1 controls
spindle checkpoint arrest and Plk1-mediated formation of the
3F3/2 epitope. J Cell Biol. 2007 Nov 19;179(4):611-7
Kang J, Yang M, Li B, Qi W, Zhang C, Shokat KM, Tomchick
DR, Machius M, Yu H. Structure and substrate recruitment of
the human spindle checkpoint kinase Bub1. Mol Cell. 2008
Nov 7;32(3):394-405
Vanoosthuyse V, Valsdottir R, Javerzat JP, Hardwick KG.
Kinetochore targeting of fission yeast Mad and Bub proteins is
essential for spindle checkpoint function but not for all
chromosome segregation roles of Bub1p. Mol Cell Biol. 2004
Nov;24(22):9786-801
Bolanos-Garcia VM, Kiyomitsu T, D'Arcy S, Chirgadze DY,
Grossmann JG, Matak-Vinkovic D, Venkitaraman AR,
Yanagida M, Robinson CV, Blundell TL. The crystal structure
of the N-terminal region of BUB1 provides insight into the
mechanism of BUB1 recruitment to kinetochores. Structure.
2009 Jan 14;17(1):105-16
Lampson MA, Kapoor TM. The human mitotic checkpoint
protein BubR1 regulates chromosome-spindle attachments.
Nat Cell Biol. 2005 Jan;7(1):93-8
Vaur S, Cubizolles F, Plane G, Genier S, Rabitsch PK, Gregan
J, Nasmyth K, Vanoosthuyse V, Hardwick KG, Javerzat JP.
Control of Shugoshin function during fission-yeast meiosis.
Curr Biol. 2005 Dec 20;15(24):2263-70
McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabé AM,
Helmhart W, Kudo NR, Wuensche A, Taylor S, Hoog C, Novak
B, Nasmyth K. Regulation of APC/C activity in oocytes by a
Bub1-dependent spindle assembly checkpoint. Curr Biol. 2009
Mar 10;19(5):369-80
Wong OK, Fang G. Loading of the 3F3/2 antigen onto
kinetochores is dependent on the ordered assembly of the
spindle checkpoint proteins. Mol Biol Cell. 2006
Oct;17(10):4390-9
Bolanos-Garcia VM, Blundell TL. BUB1 and BUBR1:
multifaceted kinases of the cell cycle. Trends Biochem Sci.
2011 Mar;36(3):141-50
Boyarchuk Y, Salic A, Dasso M, Arnaoutov A. Bub1 is
essential for assembly of the functional inner centromere. J
Cell Biol. 2007 Mar 26;176(7):919-28
This article should be referenced as such:
Bolanos-Garcia VM, Blundell TL. BUB1 (budding uninhibited
by benzimidazoles 1 homolog (yeast)). Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(1):7-11.
Kiyomitsu T, Obuse C, Yanagida M. Human Blinkin/AF15q14 is
required for chromosome alignment and the mitotic checkpoint
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
11
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
FAU (Finkel-Biskis-Reilly murine sarcoma virus
(FBR-MuSV) ubiquitously expressed)
Mark Pickard
Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, ST5 5BG, UK
(MP)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/FAUID40538ch11q13.html
DOI: 10.4267/2042/47260
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
regulation, respectively. In human cells, ectopic FAU
expression enhances basal apoptosis, whereas siRNAmediated silencing of FAU gene expression induces
resistance to apoptosis induction in response to a range
of stimuli. FAU gene expression is down-regulated in a
number of human cancers, including breast, prostate
and ovarian cancers.
Identity
Other names: FAU1, FLJ22986, Fub1, Fubi,
MNSFbeta, RPS30, asr1
HGNC (Hugo): FAU
Location: 11q13.1
Local order: FAU is flanked by SYVN1 and ZNHIT2
on the negative strand.
Note
FAU was originally identified as the cellular
homologue of the fox gene of the retrovirus FinkelBiskis-Reilly murine sarcoma virus (FBR-MuSV); fox
is antisense to FAU, and has been shown to increase
the tumorigenicity of FBR-MuSV. FAU encodes a
ubiquitin-like protein fused to ribosomal protein S30 as
a carboxy-terminal extension; the two products are
thought to be cleaved post-translationally. The S30
protein is a member of the S30E family of ribosomal
proteins and is a constituent of the 40S subunit of the
ribosome; additionally it is secreted and has antimicrobial activity ('ubiquicidin'). The function of the
ubiquitin-like protein, termed FUBI, is unclear; in
murine cells, it has been reported to covalently modify
inter alia a T-cell receptor alpha-like protein and Bcl-G,
suggestive of roles in immunomodulation and apoptosis
DNA/RNA
Description
Gene is located on the negative strand at -64889908: 64887863 (2046 bases). The promoter contains a
number of regulatory elements, including binding sites
for transcription factors such as AP-1, IRF-1, Max, cMyc, glucocorticoid receptor isoforms and ATF.
Transcription
Comprises 5 exons spanning -64888099: -64889672.
The mRNA product length is 579 bases.
Pseudogene
A retropseudogene, FAU1P, has been described in the
human genome and is located on chromosome 18.
Retropseudogenes of FAU have also been described in
the mouse genome.
FAU comprises 5 exons - the coding sequence for FUBI is located within exons 2 and 3, whereas the coding sequence for S30 is located
within exons 4 and 5.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
12
FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)
Pickard M
A. Protein products of FAU - FAU encodes a ubiquitin-like protein (FUBI) with ribosomal protein S30 as a C-terminal extension protein
(CEP). These are cleaved post-translationally. B. FUBI has 37/57% sequence identity/similarity to ubiquitin (Ub; latter is fused to
CEP80/S27a ribosomal protein). The C-terminal G-G dipeptide (shown in orange), which is required for cleavage from the CEP and for
isopeptide bond formation to lysine of targets, is conserved. Note however, that lysine residues (shown in green) which serve as sites for
polyubiquitin chain formation are absent. Consequently, FUBI is unlikely to have an analogous role to ubiquitin in protein degradation.
of target proteins. Little information exists regarding
target proteins for FUBI in human cells. In mouse, four
target proteins have been identified. Covalent
modification occurs for: (i) a T-cell receptor alpha-like
protein (resulting in the production of murine
monoclonal non-specific suppressor factor, which
exhibits immunomodulatory activity); (ii) Bcl-G (a proapoptotic member of the Bcl-2 family; and (iii)
endophilin II (regulates phagocytosis in mouse
macrophages). Non-covalent modification of histone
2A has also been reported.
Protein
Description
The protein product comprises a ubiquitin-like protein,
FUBI, with ribosomal protein S30 as a carboxyterminal extension protein (CEP); other ribosomal
proteins are produced as CEPs fused to ubiquitin. FUBI
and S30 are thought to be cleaved post-translationally,
but the enzyme catalyzing this step has not been
identified. Whilst FUBI shows a high degree of
sequence similarity to ubiquitin, notably retaining the
C-terminal G-G dipeptide motif that is required for
isopeptide bond formation between ubiquitin and
lysines of target proteins, it lacks internal lysine
residues (especially lysine-48) which serve as sites of
polyubiquitin chain formation and usually facilitate
proteasomal degradation of target molecules. Rather,
modification of proteins with monomers of ubiquitin or
ubiquitin-like proteins may influence the activity,
intracellular localisation or inter-molecular interactions
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Expression
Steady state FAU mRNA levels are highly abundant
and largely invariant in normal tissues indicative of a
house-keeping gene role. However, physiological
variations occur in FAU expression, notably in
endometrium. FAU transcript levels have been reported
to be reduced in a number of human cancers, including
those affecting the breast, the prostate and the ovary.
13
FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)
mitogen-stimulated T- and B-cells, immunoglobulin
secretion by B-cells in an isotype-specific manner (IgE
and IgG3 are especially affected), TNFalpha
production by activated macrophages and interleukin-4
secretion by bone marrow-derived mast cells and by a
type-2 helper T-cell clone (Nakamura et al., 1988;
Nakamura et al., 1994; Xavier et al., 1994; Nakamura
et al., 1995; Xavier et al., 1995; Nakamura et al., 1996;
Suzuki et al., 1996). Inhibitory effects on T- and B-cell
proliferation are subject to negative regulation by
interleukin-2 (Nakamura et al., 1988). Many of these
immunosuppresive effects of MNSF can be ascribed to
the MNSFbeta subunit, and specifically to FUBI (aka
Ubi-L) (Nakamura et al., 1996). Cell surface receptors
for MNSF have been described in target cells
(Nakamura et al., 1992), and these exhibit similarities
to cytokine receptors (Nakamura and Tanigawa, 1999),
with tyrosine phosphorylation being implicated in
transmembrane signalling (Nakamura and Tanigawa,
2000; Nakamura et al., 2002). Both the expression of
cell surface receptors on target cells and the secretion
of MNSFbeta/FUBI by splenocytes are stimulated by
interferon-gamma (Nakamura et al., 1992; Nakamura et
al., 1996). In splenocytes, FUBI conjugates to a range
of intracellular proteins, including a T-cell receptoralpha-like molecule; the resulting complex, which
comprises intact MNSF, is secreted by cells (Nakamura
et al., 1998; Nakamura et al., 2002). FUBI also
covalently modifies Bcl-G in spleen but not in testis,
despite high levels of Bcl-G expression in the latter
tissue (Nakamura and Tanigawa, 2003). In
macrophages, the FUBI/Bcl-G adduct binds to ERKs
and inhibits ERK activation by MEK1 (Nakamura and
Yamaguchi, 2006). In liver and macrophages, FUBI
also forms an adduct with endophilin II and inhibits
phagocytosis by macrophages (Nakamura and
Shimosaki, 2009; Nakamura and Watanabe, 2010).
Host defence
An anti-microbial protein, termed ubiquicidin, has been
isolated from the cytosol of a mouse macrophage cell
line treated with interferon-gamma; the protein is active
against
Listeria
monocytogenes,
Salmonella
typhimurium, Escherichia coli, Staphylococcus aureus
and Yersinia enterocolitica (Hiemstra et al., 1999).
Ubiquicidin is identical to FAU-encoded ribosomal
protein S30 (Hiemstra et al., 1999). Ubiquicidin is also
produced by human colonic mucosa (Tollin et al.,
2003) and rainbow trout skin (Fernandes and Smith,
2002). It is also active against methicillin-resistant
Staphylococcus aureus and accumulates at sites of
infection in mice (Brouwer et al., 2006). Radiolabelled
ubiquicidin has applications in clinical imaging for
microbial infections (Brouwer et al., 2008).
Localisation
Cytosolic, ribosomal and nuclear localisations have
been reported for FAU products. In addition, secretion
of FUBI (in association with a T-cell receptor-alphalike molecule) has been reported for some immune
system cell types.
Function
FAU regulates apoptosis in human epithelial and T-cell
lines. It also possesses immunomodulatory and antimicrobial activities, and encodes a constituent of the
ribosome.
Regulation of apoptosis
Functional expression cloning in mouse leukemic cell
lines, with selection (dexamethasone and gammairradiation) for suppression of cell death, led to the
isolation of a sequence which was antisense to FAU
(Mourtada-Maarabouni et al., 2004). Subcloning
experiments confirmed that this antisense sequence
produced resistance to apoptosis induced by
dexamethasone and, additionally, by cisplatin and by
ultraviolet-C irradiation. The antisense sequence
reduced endogenous FAU expression. Conversely,
overexpression of FAU promoted cell death, and this
effect could be prevented by co-transfection with a
plasmid encoding Bcl-2 (an anti-apoptotic factor) or by
inhibition of caspases. Further work in human T-cell
lines and the epithelial cell line, 293T/17, has
confirmed that ectopic FAU expression increases basal
apoptosis, and that siRNA-mediated silencing of FAU
attenuates apoptosis in response to ultraviolet-C
irradiation (Pickard et al., 2011). FAU also regulates
apoptosis in other human epithelial cell lines derived
from breast (Pickard et al., 2009), ovarian (Moss et al.,
2010) and prostate (Pickard et al., 2010) tumours (see
'Implicated in'). FUBI has been shown to covalently
modify Bcl-G (a pro-apoptotic member of the Bcl-2
family) in mouse cells (Nakamura and Tanigawa,
2003), and it is feasible therefore, that FAU regulates
apoptosis via Bcl-G. Indeed, prior knockdown of Bcl-G
ablated the stimulation of basal apoptosis by FAU in
human cells (Pickard et al., 2011). This pro-apoptotic
activity may underlie the putative tumour suppressor
role of FAU, since failure of apoptosis is known to play
a central role in the development of many cancers.
Immunomodulation
Monoclonal non-specific suppressor factor (MNSF)
was first isolated from mouse cells in 1986 (Nakamura
et al., 1988) and subsequently, from ascites fluid of a
patient with systemic lupus erythematosus (Xavier et
al., 1994); most studies of MNSF to-date have focussed
on murine cells. This lymphokine-like molecule, which
comprises alpha- and beta-chains, is secreted by CD8+
T-cells (Xavier et al., 1995). cDNA encoding MNSFbeta was first isolated from the mouse in 1995, and it
was shown to be identical to FAU (Nakamura et al.,
1995). MNSF inhibits, inter alia, proliferation of
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Pickard M
Homology
At the amino acid level, FUBI has 37/57% sequence
identity/similarity to ubiquitin.
14
FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)
Pickard M
Implicated in
simultaneously silenced, consistent with a role for BclG in mediating the pro-apoptotic activity of FAU.
Various cancers
Ovarian cancer
Note
Tumor suppression: The retrovirus, FBR-MuSV,
which contains the transduced genes v-fos and fox, can
induce osteosarcomas in mice. In vitro experiments
have shown that fox increases the transforming
capacity of FBR-MuSV approximately two-fold
(Michiels et al., 1993). Fox is an antisense sequence to
the cellular gene FAU, indicative of a tumour
suppressor role for FAU. Retropseudogenes of FAU
have been identified in human (Kas et al., 1995) and
mouse (Casteels et al., 1995) genomes, suggesting a
possible source for the viral fox gene (which is
antisense to FAU). Further evidence for a tumour
suppressor role for FAU has come from studies of the
human carcinogen arsenite. Thus, functional cloning
approaches in Chinese hamster V79 cells with selection
for arsenite resistance, resulted in the isolation of the
asr1 gene, which is homologous to FAU (Rossman and
Wang, 1999). Subsequent work by this group using
human osteogenic sarcoma cells, indicated that the
ability to confer arsenite resistance resided in the S30
domain of FAU (Rossman et al., 2003).
Oncogenesis
Expression of the FUBI domain of FAU has been
shown to transform human osteogenic sarcoma cells to
anchorage-independent growth (Rossman et al., 2003).
Note
A reduction in FAU gene expression has been reported
for malignant versus normal ovarian tissue, and for
Type I ovarian tumours (typically include mucinous,
endometrioid, clear cell, and low-grade serous cancers),
in particular (Moss et al., 2010). Over-expression of
FAU in a cisplatin-resistant ovarian cancer cell subline, A2780cis, resulted in increased sensitivity to
carboplatin-induced apoptosis (Moss et al., 2010).
Conversely, down-regulation of FAU in the A2780
parental cell line resulted in increased resistance to
carboplatin-induced apoptosis (Moss et al., 2010).
These in vitro findings suggest a role for FAU in the
regulation of platinum-based drug resistance in ovarian
cancer.
Prostate cancer
Note
Steady state FAU mRNA levels are down-regulated in
prostate cancer when compared with normal tissue and
tissue from patients with benign prostate hyperplasia; a
similar trend was found for Bcl-G (Pickard et al.,
2010). siRNA-mediated silencing of FAU or Bcl-G
expression in the prostate cell line, 22Rv1, attenuated
apoptosis induction consequent upon ultraviolet-C
irradiation. A similar degree of apoptosis resistance
was observed when the two genes were simultaneously
down-regulated, consistent with FAU and Bcl-G acting
in the same pathway.
Breast cancer
Note
Serial analysis of gene expression (SAGE) identified
FAU as an underexpressed gene in ductal carcinoma in
situ when compared with normal breast epithelium
(Abba et al., 2004). This was subsequently confirmed
using quantitative RT-PCR analysis of matched (same
patient) samples of breast cancer tissue and adjacent
breast epithelial tissue (Pickard et al., 2009).
Furthermore, in a separate group of breast cancer
patients, expression levels of FAU (determined by
cDNA microarray analysis) were shown to be related to
patient survival in Kaplan-Meier analyses (Pickard et
al., 2009). This analysis indicated that higher
expression of Fau has a protective effect, consistent
with its candidate tumour suppressor role. Whilst Bcl-G
expression was also shown to be down-regulated in
breast cancer, Bcl-G expression was not related to
patient survival (Pickard et al., 2009), suggesting that
the regulation of Bcl-G activity by post-translational
modification is more important than Bcl-G expression
per se in determining breast cancer patient survival.
Functional studies in the T-47D breast cancer cell line
demonstrated that down-regulation of either FAU or
Bcl-G expression by siRNA-mediated silencing
attenuated apoptosis induction by ultraviolet-C
irradiation (Pickard et al., 2009). Notably, no additional
effect was observed when the two genes were
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Reproduction (implantation)
Note
FAU is expressed in endometrial stromal cells in nonpregnant mouse uterus (Salamonsen et al., 2002) and it
is also expressed in human endometrium (Nie et al.,
2005). In the mouse uterus, differential expression of
FAU occurs during blastocyst implantation, with low
expression levels noted in implantation versus
interimplantation sites (Nie et al., 2000). Expression
levels remain low as implantation advances (Nie et al.,
2000). Administration of antisera to FAU into the
mouse uterine lumen inhibits implantation in a dosedependent manner (Wang et al., 2007), suggesting an
essential role for secreted products in implantation.
Trophoblast-derived interferons have been shown to
induce endometrial FAU expression in pigs (Chwetzoff
and d'Andrea, 1997), also supporting an important role
for FAU in early pregnancy.
Breakpoints
Note
A t(11;14)(q13;q21)-positive B-cell non-Hodgkin's
lymphoma patient has been described with an
additional translocation of t(11;17)(q13;q21). The
15
FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed)
Nakamura M, Xavier RM, Tsunematsu T, Tanigawa Y.
Molecular cloning and characterization of a cDNA encoding
monoclonal nonspecific suppressor factor. Proc Natl Acad Sci
U S A. 1995 Apr 11;92(8):3463-7
chromosome 11 breakpoint in the latter translocation
was reported as a 40 kbp region around FAU.
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Kas K, Michiels L, Merregaert J. Genomic structure and
expression of the human fau gene: encoding the ribosomal
protein S30 fused to a ubiquitin-like protein. Biochem Biophys
Res Commun. 1992 Sep 16;187(2):927-33
Nakamura M, Ogawa H, Tsunematsu T. IFN-gamma enhances
the expression of cell surface receptors for monoclonal
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Chwetzoff S, d'Andrea S. Ubiquitin is physiologically induced
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Kas K, Schoenmakers E, van de Ven W, Weber G,
Nordenskjöld M, Michiels L, Merregaert J, Larsson C.
Assignment of the human FAU gene to a subregion of
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Conjugation of ubiquitin-like polypeptide to intracellular
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5;1401(3):319-28
Michiels L, Van der Rauwelaert E, Van Hasselt F, Kas K,
Merregaert J. fau cDNA encodes a ubiquitin-like-S30 fusion
protein and is expressed as an antisense sequence in the
Finkel-Biskis-Reilly murine sarcoma virus. Oncogene. 1993
Sep;8(9):2537-46
Nakamura M, Tanigawa Y. Ubiquitin-like polypeptide
conjugates to acceptor proteins in concanavalin A- and
interferon gamma-stimulated T-cells. Biochem J. 1998 Mar
1;330 ( Pt 2):683-8
Olvera J, Wool IG. The carboxyl extension of a ubiquitin-like
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V, Weier U, Van den Berghe H, Van de Ven WJ. Molecular
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van Furth R. Ubiquicidin, a novel murine microbicidal protein
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Ubiquitin-like polypeptide inhibits the proliferative response of
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characterization of a human nonspecific suppressor factor from
ascitic fluid of systemic lupus erythematosus. Evidence for a
human counterpart of the monoclonal nonspecific suppressor
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Fau gene: genomic structure, chromosomal localization, and
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Findlay JK. Identification of monoclonal nonspecific suppressor
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endometrial genes of importance for implantation. J Reprod
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Immunoneutralization of endometrial monoclonal nonspecific
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the Bcl2 family. Eur J Biochem. 2003 Oct;270(20):4052-8
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Regulation of apoptosis by fau revealed by functional
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Ubiquitin-like
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MNSFβ/endophilin II complex regulates Dectin-1-mediated
phagocytosis and inflammatory responses in macrophages.
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cAMP-induced p38 MAPK activation in Th2 cells.
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regulators Fau and Bcl-G are down-regulated in prostate
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This article should be referenced as such:
Pickard M. FAU (Finkel-Biskis-Reilly murine sarcoma virus
(FBR-MuSV) ubiquitously expressed). Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(1):12-17.
Brouwer CP, Bogaards SJ, Wulferink M, Velders MP, Welling
MM. Synthetic peptides derived from human antimicrobial
peptide ubiquicidin accumulate at sites of infections and
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
17
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
GUCY2C (guanylate cyclase 2C (heat stable
enterotoxin receptor))
Stephanie Schulz, Scott A Waldman
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia,
PA, USA (SS, SAW)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/GUCY2CID43303ch12p13.html
DOI: 10.4267/2042/47261
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: GUC2C, STAR
HGNC (Hugo): GUCY2C
Location: 12p13.1
Local order: ATF7IP - PLBD1 - GUCY2C - H2AFJ HIST4H4.
Note
GUCY2C encodes a guanylyl cyclase.
DNA/RNA
Expression
Description
Localisation
The GUCY2C gene is approximately 84 kb in length
and has 27 exons.
Apical membrane.
Description
1073 amino acid protein with guanylyl cyclase catalytic
activity (4.6.1.2).
Primarily intestinal epithelial cells.
Function
Transcription
In response to binding endogenous hormones guanylin
and uroguanylin, or the exogenous ligand E. coli heatstable enterotoxin, GUCY2C synthesizes cyclic GMP.
Cyclic GMP activates downstream signaling pathways
via
cGMP-dependent
protein
kinases,
phosphodiesterases and cGMP-gated ion channels.
An approximately 3.8 mRNA is transcribed from the
gene.
Pseudogene
None known.
Homology
Adenylyl cyclase.
Image from NCBI.
Image from Ensembl.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
18
GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))
Schulz S, Waldman SA
SP: signal peptide; ECD: extracellular ligand binding domain; TM: transmembrane domain; KHD: regulatory kinase-homology domain;
CAT: guanylyl cyclase catalytic domain; TAIL: C-terminal tail, interacts with scaffolding proteins.
Implicated in
proliferating compartment in intestine. Am J Pathol. 2007
Dec;171(6):1847-58
Colorectal cancer
Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y,
Baran AA, Siracusa LD, Pitari GM, Waldman SA. Guanylyl
cyclase C suppresses intestinal tumorigenesis by restricting
proliferation
and
maintaining
genomic
integrity.
Gastroenterology. 2007 Aug;133(2):599-607
Note
The endogenous GUCY2C ligands, guanylin and
uroguanylin, are lost early in the neoplastic process.
Targeted deletion of Gucy2c in mice results in a
phenotype of intestinal cancer susceptibility in the
context of predisposing genetic mutations (apcmin) or
exposure to carcinogen (azoxymethane).
Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM,
Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA. The
hormone receptor GUCY2C suppresses intestinal tumor
formation by inhibiting AKT signaling. Gastroenterology. 2010
Jan;138(1):241-54
References
This article should be referenced as such:
Schulz S, Waldman SA. GUCY2C (guanylate cyclase 2C (heat
stable enterotoxin receptor)). Atlas Genet Cytogenet Oncol
Haematol. 2012; 16(1):18-19.
Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM.
Homeostatic control of the crypt-villus axis by the bacterial
enterotoxin receptor guanylyl cyclase C restricts the
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
19
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
LIN28B (lin-28 homolog B (C. elegans))
Yung-Ming Jeng
Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University,
Taipei, Taiwan (YMJ)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/LIN28BID45723ch6q16.html
DOI: 10.4267/2042/47262
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
It inhibits biosynthesis of let-7 microRNA through
promoting terminal uridylation of let-7 precusor by
TUTase4.
Other names: CSDD2, FLJ16517, Lin28.2
HGNC (Hugo): LIN28B
Location: 6q16.3
Note
Size: 146,72 kb. Orientation: plus strand.
Homology
Lin28
Mutations
DNA/RNA
Note
No somatic mutation of Lin28B was identified in
cancer.
Description
The gene spans over 125 kb on plus strand; 4 exons.
Transcription
Implicated in
The gene is mainly expressed in fetal tissues and not
expressed in adult tissue and reexpressed in cancer
tissue.
Hepatocellular carcinoma
Note
Lin28B expression is more frequently noted in highgrade hepatocellular carcinoma with high alphafetoprotein levels. Knockdown of Lin28B by RNA
interference in the HCC cell line suppressed
proliferation in vitro and reduced in vivo tumor growth
in NOD/SCID mice. In contrast, overexpression of
Lin28B in the HCC cell line enhanced tumorigenicity.
Overexpression of Lin28B also induced epithelialmesenchymal transition in HA22T cells and hence,
invasion capacity.
Protein
Description
Lin28B is an oncofetal RNA-binding protein. Lin-28B
protein consists of two domains that contain RNAbinding motif: the N-terminal cold shock domain and a
pair of retroviral-type CCHC zinc fingers. It inhibits
biosynthesis of let-7 microRNA through binding to the
5'-GGAG-3' motif in the terminal loop of pre-let-7 and
promoting terminal uridylation of let-7 precusor by
TUTase4. Uridylated pre-let-7 miRNAs fail to be
processed by Dicer and undergo degradation.
Colorectal cancer
Note
Lin28B is overexpressed in colorectal cancer. It
promotes cell migration, invasion and transforms
Expression
Cytoplasm.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
20
LIN28B (lin-28 homolog B (C. elegans))
Jeng YM
immortalized colonic epithelial cells. In addition,
constitutive LIN28B expression increases expression of
intestinal stem cell markers LGR5 and PROM1 in the
presence of let-7 restoration.
He C, Kraft P, Chen C, Buring JE, Paré G, Hankinson SE,
Chanock SJ, Ridker PM, Hunter DJ, Chasman DI. Genomewide association studies identify loci associated with age at
menarche and age at natural menopause. Nat Genet. 2009
Jun;41(6):724-8
Ovarian cancer
Lu L, Katsaros D, Shaverdashvili K, Qian B, Wu Y, de la
Longrais IA, Preti M, Menato G, Yu H. Pluripotent factor lin-28
and its homologue lin-28b in epithelial ovarian cancer and their
associations with disease outcomes and expression of let-7a
and IGF-II. Eur J Cancer. 2009 Aug;45(12):2212-8
Note
Lin28B is overexpressed in high grade serous ovarian
cancer. Pleomorphism in Lin28B promoter region is
associated with susceptibility to epithelium ovarian
cancer. Patients with high Lin28B ovarian cancer had
shorter progression-free and overall survival than those
with low Lin28B ovarian cancer.
Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL,
Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL, Shah
SP, Tanwar PS, Mermel CH, Beroukhim R, Azam M, Teixeira
J, Meyerson M, Hughes TP, Llovet JM, Radich J, Mullighan
CG, Golub TR, Sorensen PH, Daley GQ. Lin28 promotes
transformation and is associated with advanced human
malignancies. Nat Genet. 2009 Jul;41(7):843-8
Age at menarche
Note
A sequence variation in Lin28B is identified as the
SNP most significant associated with age at menarche
in one genome wide study. Besides, a meta-analysis of
32 genome-wide association studies in 87802 women
found polymorphism of Lin28B is strongly associated
with age at menarche. Knockout mice of Lin28B also
show delay in puberty onset.
Helland Å, Anglesio MS, George J, Cowin PA, Johnstone CN,
House CM, Sheppard KE, Etemadmoghadam D, Melnyk N,
Rustgi AK, Phillips WA, Johnsen H, Holm R, Kristensen GB,
Birrer MJ, Pearson RB, Børresen-Dale AL, Huntsman DG,
deFazio A, Creighton CJ, Smyth GK, Bowtell DD. Deregulation
of MYCN, LIN28B and LET7 in a molecular subtype of
aggressive high-grade serous ovarian cancers. PLoS One.
2011 Apr 13;6(4):e18064
King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS,
Rustgi AK. LIN28B promotes colon cancer progression and
metastasis. Cancer Res. 2011 Jun 15;71(12):4260-8
Body height
Note
A LIN28B SNP, rs314277, is associated with final
body height.
King CE, Wang L, Winograd R, Madison BB, Mongroo PS,
Johnstone CN, Rustgi AK. LIN28B fosters colon cancer
migration, invasion and transformation through let-7-dependent
and -independent mechanisms. Oncogene. 2011 Oct
6;30(40):4185-93
References
This article should be referenced as such:
Heo I, Joo C, Cho J, Ha M, Han J, Kim VN. Lin28 mediates the
terminal uridylation of let-7 precursor MicroRNA. Mol Cell.
2008 Oct 24;32(2):276-84
Jeng YM. LIN28B (lin-28 homolog B (C. elegans)). Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(1):20-21.
Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of
microRNA processing by Lin28. Science. 2008 Apr
4;320(5872):97-100
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
21
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PKD1 (polycystic kidney disease 1 (autosomal
dominant))
Ying-Cai Tan, Hanna Rennert
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College 1300 York Street, F701
New York, NY 10065, USA (YCT, HR)
Published in Atlas Database: July 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/PKD1ID41725ch16p13.html
DOI: 10.4267/2042/47263
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
The 14,5 kb transcript has two different isoforms as a
result of alternative splicing. The longer variant,
isoform I (NM_001009944), has a 12909 bp open
reading frame. The short variant, isoform II
(NM_000293), uses an alternate acceptor splice site, 3
nt downstream of that used by isoform I, at the junction
of intron 31 and exon 32. This results in an isoform
(variant II) that is one amino acid shorter than isoform
I.
Other names: PBP, Pc-1, polycystin-1, TRPP1
HGNC (Hugo): PKD1
Location: 16p13.3
DNA/RNA
Description
This gene has 46 exons that span ~52 kb of genomic
sequence. Exons 1-33 are located in a genomic region
which is duplicated six times on the same chromosome
(~13-16 Mb proximal to PKD1 on the short arm of
chromosome 16), resulting in six pseudogenes. A
Mirtron family microRNA gene, miR-1225, is lying
within intron 45 of PKD1, the function of this
microRNA is currently unknown.
Pseudogene
The six pseudogenes that result from duplication of
PKD1 exon 1 through 33 are located on chromosome
16p13.1 and have 97-99% identity to PKD1. Those
pseudogenes are transcripted into mRNA species with
suboptimal start codons, thus they are not translated.
Ideogram of human chromosome 16, the location of PKD1 gene is indicated by the red vertical line. This graph was generated by using
UCSC genome browser.
Gene structure of PKD1, showing the intron/exon structure. Exons are shown with solid box; introns are shown with thin line arrow heads;
3' and 5' UTR regions are indicated by open boxes. Some exons numbers are labelled above. This graph was generated by using UCSC
genome browser.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
22
PKD1 (polycystic kidney disease 1 (autosomal dominant))
Tan YC, Rennert H
Protein structure of polycystin-1 (PC1). The details of the protein domain structures are shown. Abreviation: GPS, GPCR Proteolystic
Site; WSC, cell Wall integrity and Stress response Component; PLAT, (Polycystin-1, Lipoxygenase, Alpha-Toxin); REJ, Receptor for Egg
Jelly. This graph was generated by using ExPASY Proteomics Server PROSITE module with some modifications.
Function
Protein
In the kidney tubule, polycystin-1 was shown to serve
as a mechanoreceptor that senses fluid flow in the
tubular lumen, triggering Ca2+ influx through
polycystin-2, a Ca2+ channel that interact with PC1 in
the C-terminal tail, consequently affecting the
intracellular calcium and cyclic AMP (cAMP) levels. It
is also involved in cell-to-cell or cell-to-matrix
interactions.
Description
The longer form of polycystin-1, isoform I, has 4303
aa. It is a 460 kDa membrane protein which has the
structure of a receptor or adhesion molecule. The large
extracellular N-terminal region consisting of a variety
of domains, including 12 PKD domains (an
immunoglobin-like fold), two leucine-rich repeats, Ctype lectin domain, WSC domain, GPS domain and
REJ domain. The short intracellular C-terminal region
has 197 aa, containing a coiled-coil domain that
interact with polycystin-2 and a G-protein binding
domain. Between the N and C-terminal is a large
transmembrane region (1032 aa) that has 11
transmembrane domains. Polycystin-1 is cleaved at the
G protein-coupled receptor proteolytic site (GPS)
domain, resulting in a 150 kDa C-terminal fragment
and a 400 kDa N-terminal fragment that tether to the
membrane. This cleavage is suggested to be important
for protein activation.
Homology
The characterized domains of polycystin-1 are regions
highly conserved among species (from human to fish).
A homology and also an interaction partner in the same
signaling passway, polycystin-2, is located on 4q21.
Mutations
Germinal
Autosomal dominant polycystic kidney disease
(ADPKD) is the most common inherited kidney
disease. Up to 85% of ADPKD cases are caused by
mutations in PKD1 gene. With the current mutation
detection methods, definite pathogenic mutations
(nonsense, truncation and canonical splice defects) are
identified in approximately 60% of the cases. Large
deletions/insertions can be found in ~4% of cases.
Comprehensive analyses, using bioinformatics analysis
tools can identify missense mutations that may account
for the disease in an additional 22% to 37% of the
ADPKD patients. There are no mutation hot spots for
PKD1, which means mutations are usually private, with
70% of the mutations unique to a single family, and
spread throughout the entire gene. Mutations on 5' of
the gene are associated with a more sever disease
compared to those occurring in 3' region. The ADPKD
Mutation
Database
at
Mayo
Clinic
(http://pkdb.mayo.edu/), the most complete one for
Expression
Polycystin-1 is widely expressed in adult tissue, with
high levels in brain and moderate expression in kidney.
In fetal and adult kidney, the expression was restricted
to the epithelial cells with highest expression in the
embryo and downregulation in adult. In smooth,
skeletal and cardiac muscles, expression is also found.
Localisation
Polycystin-1 is located in the primary cilium, a single
hair-like organelle projecting from the surface of most
mammalian cells. It is also found in the plasma
membrane at focal adhesions, desmosomes, and
adherens junctions. The C-terminal tail of PC1 has
been reported to be cleaved and migrate to the nucleus,
regulating gene expression.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
23
PKD1 (polycystic kidney disease 1 (autosomal dominant))
Tan YC, Rennert H
ADPKD, documents 416 pathogenic mutations for
PKD1 in a total of 616 families.
enlarged, cystic kidneys to incidental diagnosis in the
elderly with adequate renal function. Extra-renal
manifestations include cysts in the liver, pancreas,
seminal vesicles and arachnoid membranes. Intracranial
aneurysm is about five times more common than in the
general population and is associated with significant
morbidity and mortality.
Prognosis
About 50% of patients with ADPKD will progress to
end stage renal disease (ESRD) by the age of 60 years,
with hemodialysis or kidney transplant being the only
currently available treatment, though several potential
drugs have been entered into clinical trials.
Hypertension is present in about 50% of ADPKD
patients age 20-30 years with clinically normal renal
function; this is approximately one decade earlier than
the onset of primary hypertension in the general
population.
Somatic
The pathogenesis of ADPKD has been attributed to a
two-hit mechanism, with somatic and germline
mutations combining to inactivate one of the PKD
genes, leading to loss of function, thus initiating the
disease process. There are significantly less somatic
PKD mutations listed in the ADPKD Mutation
Database, only 9 for PKD1 (http://pkdb.mayo.edu/).
Due to the limited availability of kidney cyst DNA and
the complications associated with PKD1 genotyping,
analyzing somatic mutations in ADPKD was proven to
be difficult.
Implicated in
Autosomal dominant polycystic kidney
disease (ADPKD)
References
Disease
ADPKD is a monogenic multi-systemic disorder
characterized by age-dependent development and
progressive enlargement of bilateral, multiple renal
cysts, resulting in chronic renal failure typically in mid
to late adulthood. The cysts are caused by abnormal
proliferation of renal tubule epithelial cells as a result
of inactivation of the PKD genes by mutations.
Mutations in PKD1 gene account for 85% of the
ADPKD cases and for the early-onset, more sever
form. Those cysts will increase gradually in both size
and number, leading to massive kidney enlargement
and progressive decline in renal function. ADPKD has
a prevalence of approximately 1 in 400 to 1 in 1000
live births in all races, affecting approximately 12,5
million individuals worldwide. Although ADPKD
accounts for 4,4% of all patients requiring renal
replacement therapy, it is characterized by very large
phenotypic variability, ranging from presentation inutero with
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Wilson PD. Polycystic kidney disease. N Engl J Med. 2004 Jan
8;350(2):151-64
Torres VE, Harris PC, Pirson Y. Autosomal dominant
polycystic
kidney
disease.
Lancet.
2007
Apr
14;369(9569):1287-301
Tan YC, Blumenfeld JD, Anghel R, Donahue S, Belenkaya R,
Balina M, Parker T, Levine D, Leonard DG, Rennert H. Novel
method for genomic analysis of PKD1 and PKD2 mutations in
autosomal dominant polycystic kidney disease. Hum Mutat.
2009 Feb;30(2):264-73
Torres VE, Harris PC. Autosomal dominant polycystic kidney
disease: the last 3 years. Kidney Int. 2009 Jul;76(2):149-68
Harris PC, Rossetti S. Molecular diagnostics for autosomal
dominant polycystic kidney disease. Nat Rev Nephrol. 2010
Apr;6(4):197-206
This article should be referenced as such:
Tan YC, Rennert H. PKD1 (polycystic kidney disease 1
(autosomal dominant)). Atlas Genet Cytogenet Oncol
Haematol. 2012; 16(1):22-24.
24
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
AMFR (autocrine motility factor receptor)
Yalcin Erzurumlu, Petek Ballar
Ege University, Faculty of Pharmacy, Biochemistry Department, Bornova, 35100, Izmir, Turkey (YE, PB)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/AMFRID627ch16q12.html
DOI: 10.4267/2042/47264
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
strand. The DNA of AMFR consists of 14 exons and
the coding sequence starts in the first exon.
Other names: GP78, RNF45
HGNC (Hugo): AMFR
Location: 16q12.2
Transcription
The AMFR gene has two transcripts. One of these
transcripts is 2249 bp long and is a processed transcript
with no protein product. 3598 bp long second AMFR
transcript is a protein coding transcript (accession
number: NM_001144). The DNA has been cloned in
1999 (Shimizu et al., 1999).
DNA/RNA
Description
The AMFR gene spans 64081 bases on minus
AMFR gene genomic location at chromosome 16q12.2 (minus strand).
A. The alignment of AMFR mRNA to its genomic sequence. B. AMFR mRNA and its amino acid coding.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
25
AMFR (autocrine motility factor receptor)
Erzurumlu Y, Ballar P
A schematic representation of the domain structure.
Expression
Protein
gp78/AMFR is relatively ubiquitously expressed in
normal human cells, especially highly in liver, heart
and lung. Northern blot analysis detected a 3.5-kb
AMFR transcript in mouse heart, brain, lung, liver,
skeletal muscle, kidney, and testis, but not in spleen
(Shimizu et al., 1999). gp78/AMFR is overexpressed in
certain malignant tumors and human cancers of the
lung, gastrointestinal tract, breast, liver, thymus, and
skin (Chiu et al., 2008; Sjöblom et al., 2006; Tsai et al.,
2007; Joshi et al., 2010).
Description
AMFR belongs to the family of RING-Finger ubiquitin
ligases. The complete protein contains 643 amino
acids. The calculated molecular weight of AMFR is
73,0 kDa.
AMFR was originally isolated as a membrane
glycoprotein from murine melanoma cells and was
implicated in cell migration (Nabi and Raz, 1987).
Subsequently, gp78/AMFR was identified as the tumor
autocrine motility factor receptor mediating tumor
invasion and metastasis (Nabi et al., 1990). A
monoclonal antibody named 3F3A was generated
against this protein and first sequence reported for
human gp78/AMFR was in 1991 using this antibody
(Watanabe et al., 1991). However, the protein product
was only 321 amino acids (Watanabe et al., 1991). A
sequence giving 643 amino acids protein product was
cloned in 1999 (Shimizu et al., 1999).
gp78/AMFR has five to seven transmembrane domains
according to different softwares like SACS MEMSAT
and SOSUI. The protein has a long cytoplasmic tail
composed of around 350 amino acids (Shimizu et al.,
1999). Besides conveying E3 activity the
multifunctional cytoplasmic tail is responsible for
interaction with polyubiquitin, ubiquitin conjugating
enzyme, p97/VCP and Ufd1. The RING finger domain
of gp78/AMFR residing between amino acids 341 and
383 is a RING-H2 type domain containing two His
residues in positions 4 and 5 (Fang et al., 2001). The
Cue domain of gp78/AMFR residing between amino
acids 456 and 497 is responsible for polyubiquitin
binding and has been identified by having homologous
sequences of yeast protein Cue1p (Ponting, 2000). The
p97/VCP-interacting motif of gp78/AMFR consists of
C-terminal amino acid residues between 614-643 and it
is sufficient to bind to p97/VCP protein (Ballar et al.,
2006). gp78/AMFR binds to its ubiquitin conjugating
enzyme via a region called UBE2G2 binding region
(G2BR) and this region is resides between amino acids
579 and 600 (Chen et al., 2006). Additionally,
gp78/AMFR interacts directly with Ufd1 through
residues 383-497 (Cao et al., 2007) and with INSIGs
through its transmembrane domains (Song et al., 2005).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Localisation
Endoplasmic
reticulum
membrane,
transmembrane protein (Fang et al., 2001).
multi-pass
Function
In 2001, it has been reported that gp78/AMFR
possesses ubiquitin ligase (E3) activity (Fang et al.,
2001) and can ubiquitinate both itself and other
proteins for proteasomal degradation. gp78/AMFR is a
member of multiprotein complex functioning in
endoplasmic reticulum associated degradation (ERAD).
gp78/AMFR not only functions as an E3 during ERAD
but also couples retrotranslocation and deglycosylation
to ubiquitination (Ballar et al., 2006; Li et al., 2005).
Homology
Homologues have been found in various species like
bovine, chimpanzee (99.8 % homology), chicken, zebra
fish, rat, C. elegans and mouse. gp78/AMFR shares
94.7 % of homology with murine gp78/AMFR.
Mutations
Somatic
D605V mutation has been reported in breast cancer
(Sjöblom et al., 2006). Several SNPs have been found
in gp78/AMFR gene both at coding regions and at
UTRs and introns. See SNP database at NCBI.
Implicated in
Sarcoma metastasis
Note
gp78/AMFR targets KAI1, a known metastasis
26
AMFR (autocrine motility factor receptor)
Erzurumlu Y, Ballar P
suppressor protein for ubiquitin mediated proteasomal
degradation (Tsai et al., 2007). Thus gp78/AMFR has
role in metastasis of human sarcoma. Furthermore, a
human sarcoma tissue microarray study documents that
tumors with low gp78 expression has higher levels of
KAI1 and high gp78 level lower KAI1 expression in
tumors (Tsai et al., 2007).
pericarcinomatous liver tissues. Furthermore, there is a
strong correlation between AMFR expression and
invasion and metastasis of HCC (Wang et al., 2007).
Bladder carcinoma
Note
While in normal urothelium gp78/AMFR is not
expressed, its expression is increased in bladder
carcinoma specimens (Otto et al., 1994).
Breast cancer
Note
gp78/AMFR expression in gp78 transgenic mammary
glands induces mammary gland hyperplasia, increases
duct number and network density and shows downregulation of KAI1 metastasis suppressor (Joshi et al.,
2010). Additionally, gp78/AMFR has been identified as
one of the most mutated genes in breast cancer
(Sjöblom et al., 2006). Consistently, gp78/AMFR is
overexpressed in human breast cancer and is negatively
associated with patients' clinical outcome (Jiang et al.,
2006).
Cardiovascular diseases and
hypercholesterolemia
Note
Accumulation of sterols in ER membranes triggers the
binding of HMG CoA reductase, the rate limiting
enzyme of cholesterol biosynthesis, to the Insig1gp78/AMFR complex which is essential for the
ubiquitination and proteasomal degradation of
HMGCoA-reductase (Goldstein et al., 2006; Jo and
DeBose-Boyd, 2010). gp78/AMFR is also the E3 ligase
of apolipoprotein B100, the protein component of
atherogenic lipoproteins, overproduction of which is a
common feature of human dyslipidemia (Liang et al.,
2003).
Gastric carcinoma
Note
gp78/AMFR expression may be associated with the
progression and invasion of gastric carcinoma as well
as the prognoses of the patients (Hirono et al., 1996).
Furthermore, by using same 3F3A antibody it was
reported that gp78/AMFR expression is associated with
lymph node metastasis and peritoneal dissemination in
gastric carcinoma (Taniguchi et al., 1998).
Cystic fibrosis
Note
gp78/AMFR degrades mutant cystic fibrosis
transmembrane conductance regulator (CFTR∆F508)
associated with cystic fibrosis (Ballar et al., 2010;
Morito et al., 2008).
Colorectal cancer
Metabolism and disposition of drugs
Note
gp78/AMFR expression is correlated high incidence of
recurrence of the patients with colorectal cancer
(Nakamori et al., 1994).
Note
gp78/AMFR participates in proteasomal degradation of
CYP3A4, a dominant human liver cytochrome P450
enzyme functioning in the metabolism and disposition
of drugs and responsible for many adverse drug-drug
interactions (Kim et al., 2010; Pabarcus et al., 2009).
Melanoma
Note
It was showed by using 3F3A antibody that
gp78/AMFR protein expression in human melanoma
cell lines correlates to their metastatic potential. While
in thin tumors weak/heterogenous gp78/AMFR
expression predominated, in thick tumors the strong
gp78/AMFR expression profile was predominant
(Tímár et al., 2002).
Chronic obstructive pulmonary disease
Note
gp78/AMFR expression is increased with the severity
of emphysema (Min et al., 2011).
Neurodegenerative diseases
Note
gp78/AMFR may play a protective role against mutant
huntingtin toxicity. Mutant huntingtin hinders
polyubiquitin binding to the cue domain of
gp78/AMFR and causes aggregation of ligase (Yang et
al., 2010). gp78/AMFR also enhances ubiquitination,
degradation, suppression of aggregation of mutant
SOD1 associated with amyotrophic lateral sclerosis
(ALS), and mutant ataxin-3 associated with MachadoJoseph disease. Furthermore, in spinal cords of ALS
mice, gp78/AMFR expression is significantly is upregulated (Ying et al., 2009).
Lung cancer
Note
Using immunohistochemical staining the gp78/AMFR
expression was showed to be associated with histologic
type of tumor, mainly in adenocarcinoma (Kara et al.,
2001).
Hepatocellular carcinoma
Note
The expression of gp78/AMFR significantly increased
in hepatocellular carcinoma compared with
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
27
AMFR (autocrine motility factor receptor)
Erzurumlu Y, Ballar P
Liang JS, Kim T, Fang S, Yamaguchi J, Weissman AM, Fisher
EA, Ginsberg HN. Overexpression of the tumor autocrine
motility factor receptor Gp78, a ubiquitin protein ligase, results
in increased ubiquitinylation and decreased secretion of
apolipoprotein B100 in HepG2 cells. J Biol Chem. 2003 Jun
27;278(26):23984-8
Alpha-1-antitrypsin deficiency
Note
gp78/AMFR targets mutant ATZ (Z-variant alpha-1antitrypsin) associated with alpha-1-antitrypsin
deficiency for the proteasomal degradation and
increases its solubility (Shen et al., 2006).
Li G, Zhou X, Zhao G, Schindelin H, Lennarz WJ. Multiple
modes of interaction of the deglycosylation enzyme, mouse
peptide N-glycanase, with the proteasome. Proc Natl Acad Sci
U S A. 2005 Nov 1;102(44):15809-14
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Song BL, Sever N, DeBose-Boyd RA. Gp78, a membraneanchored ubiquitin ligase, associates with Insig-1 and couples
sterol-regulated ubiquitination to degradation of HMG CoA
reductase. Mol Cell. 2005 Sep 16;19(6):829-40
Nabi IR, Raz A. Cell shape modulation alters glycosylation of a
metastatic melanoma cell-surface antigen. Int J Cancer. 1987
Sep 15;40(3):396-402
Nabi IR, Watanabe H, Raz A. Identification of B16-F1
melanoma autocrine motility-like factor receptor. Cancer Res.
1990 Jan 15;50(2):409-14
Ballar P, Shen Y, Yang H, Fang S. The role of a novel
p97/valosin-containing protein-interacting motif of gp78 in
endoplasmic reticulum-associated degradation. J Biol Chem.
2006 Nov 17;281(46):35359-68
Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz
A. Purification of human tumor cell autocrine motility factor and
molecular cloning of its receptor. J Biol Chem. 1991 Jul
15;266(20):13442-8
Chen B, Mariano J, Tsai YC, Chan AH, Cohen M, Weissman
AM. The activity of a human endoplasmic reticulum-associated
degradation E3, gp78, requires its Cue domain, RING finger,
and an E2-binding site. Proc Natl Acad Sci U S A. 2006 Jan
10;103(2):341-6
Silletti S, Raz A. Autocrine motility factor is a growth factor.
Biochem Biophys Res Commun. 1993 Jul 15;194(1):446-57
Nakamori S, Watanabe H, Kameyama M, Imaoka S, Furukawa
H, Ishikawa O, Sasaki Y, Kabuto T, Raz A. Expression of
autocrine motility factor receptor in colorectal cancer as a
predictor for disease recurrence. Cancer. 1994 Oct
1;74(7):1855-62
Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors
for membrane sterols. Cell. 2006 Jan 13;124(1):35-46
Jiang WG, Raz A, Douglas-Jones A, Mansel RE. Expression of
autocrine motility factor (AMF) and its receptor, AMFR, in
human breast cancer. J Histochem Cytochem. 2006
Feb;54(2):231-41
Otto T, Birchmeier W, Schmidt U, Hinke A, Schipper J, Rübben
H, Raz A. Inverse relation of E-cadherin and autocrine motility
factor receptor expression as a prognostic factor in patients
with bladder carcinomas. Cancer Res. 1994 Jun
15;54(12):3120-3
Shen Y, Ballar P, Fang S. Ubiquitin ligase gp78 increases
solubility and facilitates degradation of the Z variant of alpha-1antitrypsin. Biochem Biophys Res Commun. 2006 Nov
3;349(4):1285-93
Hirono Y, Fushida S, Yonemura Y, Yamamoto H, Watanabe H,
Raz A. Expression of autocrine motility factor receptor
correlates with disease progression in human gastric cancer.
Br J Cancer. 1996 Dec;74(12):2003-7
Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD,
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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.
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Taniguchi K, Yonemura Y, Nojima N, Hirono Y, Fushida S,
Fujimura T, Miwa K, Endo Y, Yamamoto H, Watanabe H. The
relation between the growth patterns of gastric carcinoma and
the expression of hepatocyte growth factor receptor (c-met),
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1;82(11):2112-22
Cao J, Wang J, Qi W, Miao HH, Wang J, Ge L, DeBose-Boyd
RA, Tang JJ, Li BL, Song BL. Ufd1 is a cofactor of gp78 and
plays a key role in cholesterol metabolism by regulating the
stability of HMG-CoA reductase. Cell Metab. 2007
Aug;6(2):115-28
Shimizu K, Tani M, Watanabe H, Nagamachi Y, Niinaka Y,
Shiroishi T, Ohwada S, Raz A, Yokota J. The autocrine motility
factor receptor gene encodes a novel type of seven
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Tsai YC, Mendoza A, Mariano JM, Zhou M, Kostova Z, Chen
B, Veenstra T, Hewitt SM, Helman LJ, Khanna C, Weissman
AM. The ubiquitin ligase gp78 promotes sarcoma metastasis
by targeting KAI1 for degradation. Nat Med. 2007
Dec;13(12):1504-9
Ponting CP. Proteins of the endoplasmic-reticulum-associated
degradation pathway: domain detection and function
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AMFR (autocrine motility factor receptor)
Erzurumlu Y, Ballar P
Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E,
Correia MA. CYP3A4 ubiquitination by gp78 (the tumor
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E3 ubiquitin ligases: physiological and pharmacological
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proliferation and mammary gland hyperplasia by the gp78
ubiquitin ligase. J Biol Chem. 2010 Mar 19;285(12):8830-9
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Erzurumlu Y, Ballar P. AMFR (autocrine motility factor
receptor). Atlas Genet Cytogenet Oncol Haematol. 2012;
16(1):25-29.
29
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
ASH2L (ash2 (absent, small, or homeotic)-like
(Drosophila))
Paul F South, Scott D Briggs
Department of Biochemistry and Purdue University Center for Cancer Research, Purdue University, West
Lafayette, Indiana 47907, USA (PFS, SDB)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/ASH2LID44404ch8p11.html
DOI: 10.4267/2042/47265
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
573 from isoform 1 (Wang et al., 2001). Isoform 3 is
missing the amino acids 1-94 from isoform 1 (figure 2)
(Wang et al., 2001). There are four identified domains
within ASH2L which include a N-terminus containing
a PHD finger and a winged helix motif (WH) and the
C-terminus containing a SPRY domain and the Sdc1
DPY-30 Interacting domain (SDI) (figure 2) (Chen et
al., 2011; Roguev et al., 2001; Sarvan et al., 2011;
South et al., 2010; Wang et al., 2001). The largest of
the three identified domains within ASH2L is the
SPRY domain, which is also conserved from yeast to
humans. SPRY domains were originally named after
the SPIa kinase and the RYanodine receptor proteins in
which it was first identified (Rhodes et al., 2005).
Crystal structures of SPRY domain containing proteins
show primarily a beta-sandwich structure with
extending loops (Filippakopoulos et al., 2010; Kuang et
al., 2009; Simonet et al., 2007; Woo et al., 2006b). The
SPRY domain is thought to be a specific proteinprotein interaction domain
Identity
Other names: ASH2, ASH2L1, ASH2L2, Bre2
HGNC (Hugo): ASH2L
Location: 8p11.23
DNA/RNA
Description
16 exons spanning over 34218 base pairs.
Transcription
mRNA is 2368 base pairs long.
Protein
Description
There are three known isoforms of ASH2L (Wang et
al., 2001). Isoform 1 is considered the canonical
sequence and consists of 628 amino acids (Wang et al.,
2001). Isoform 2 is missing amino acids 1-94 and 541-
Figure 1. Map of chromosome 8 with region 8p11.2 highlighted as the location of the gene ASH2L.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
30
ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila))
South PF, Briggs SD
Figure 2. Schematic model of the three known isoforms of ASH2L and the amino acid sequence changes compared to the canonical
isoform 1 (aa 1-628). The positions of known domains within ASH2L are displayed. PHD finger (aa 95-161), WH motif (aa 162-273),
SPRY domain (aa 360-583), and SDI domain (aa 602-628). Isoform 2 and 3 are numbered according to isoform 1.
with specific partners, but instead of recognizing a
particular motif or interaction domain the SPRY
domain binds to interaction partners using nonconserved binding loops (Filippakopoulos et al., 2010;
Woo et al., 2006a; Woo et al., 2006b). Recent work has
shown that the C-terminus of ASH2L that contains the
SPRY domain and the SDI domain are able to interact
with the other MLL complex member RBBP5 in vitro
(Avdic et al., 2011).
ASH2L also contains a putative Plant Homeo Domain
(PHD) finger in its N-terminus (Wang et al., 2001). The
structure of PHD fingers shows that conserved cysteine
and histidine residues bind to Zn2+ ions (Champagne et
al., 2008; Champagne and Kutateladze, 2009; van
Ingen et al., 2008). There is no known function
attributed to the PHD finger in ASH2L, though in
conjunction with the winged helix motif it may be
necessary for DNA binding.
The N-terminal winged helix (WH) motif was recently
discovered when the crystal structure of the N-terminus
of ASH2L was solved (Chen et al., 2011; Sarvan et al.,
2011). Using in vitro DNA binding analyses as well as
chromatin immunoprecipitation, it was determined that
ASH2L can bind DNA at the HS2 promoter region and
the beta-globin locus as well as non-specific DNA
sequence (Chen et al., 2011; Sarvan et al., 2011).
The last identifiable domain within ASH2L is the SDI
domain. There is no structural information on the SDI
domain but the functional importance was determined
biochemically. The function of the SDI domain was
determined using in vitro binding experiments. ASH2L
was shown to directly interact with DPY-30 without
any additional MLL or Set1 complex components
(South et al., 2010). The function of the SDI domain is
conserved from yeast to humans because the yeast
ASH2L homolog Bre2 was also shown to interact with
the DPY-30 homolog Sdc1 (South et al., 2010). There
are conserved hydrophobic residues in both the SDI
domain of ASH2L and the Dpy-30 domain of DPY-30
that are important for binding, which suggests that the
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
interaction between the SDI domain of ASH2L and the
DPY-30 domain of DPY-30 is through hydrophobic
interactions (South et al., 2010).
Expression
Northern blot analysis from multiple tissues revealed
that ASH2L expression is expressed in 14 different
tissue types with the highest expression in fetal liver
and testes (Lüscher-Firzlaff et al., 2008). ASH2L
transcripts were also found to be expressed higher in
various Leukemia cell lines, such as K562, Hel, and
Dami cells (Lüscher-Firzlaff et al., 2008).
Localisation
Nucleus.
Function
Biochemical data has shown that ASH2L is found in a
methyltransferase core complex composed of ASH2L,
RBBP5, DPY30, WDR5, and the catalytic SET domain
containing protein. This core complex is highly
conserved and similar to the budding yeast Set1
complex that consists of Set1 (MLL/SET1), Bre2
(ASH2L), Swd1 (RBBP5), Swd3 (WDR5), Swd2
(WDR82), Sdc1 (DPY-30), Spp1 (CFP1/CGBP).
ASH2L is also known to associate with numerous
additional factors. Many of these additional factors are
thought to associate with ASH2L and the H3K4
methyltransferase complexes to target the complex to
specific sites within the genome (Cho et al., 2007; Dou
et al., 2006; Hughes et al., 2004; Steward et al., 2006;
Stoller et al., 2010). Knock-down of ASH2L using
siRNA globally decreases H3K4 trimethylation (Dou et
al., 2006; Steward et al., 2006). ASH2L and H3K4
methylation both appear to play a key role in
oncogenesis (Hess, 2006). ASH2L is found to be over
abundant in many cancer cell lines and knock-down of
ASH2L by siRNA can prevent tumorigenesis (LüscherFirzlaff et al., 2008). Recent work has suggested that
ASH2L in combination with WDR5 and RBBP5
exhibits H3K4 methyltransferase activity (Cao et al.,
31
ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila))
South PF, Briggs SD
methyltransferase activity by its core components. Nat Struct
Mol Biol. 2006 Aug;13(8):713-9. Epub 2006 Jul 30.
2010; Patel et al., 2009; Patel et al., 2011). In addition,
this catalytic activity is not dependent on the SET
domain containing proteins such as MLL1 (Cao et al.,
2010; Patel et al., 2009; Patel et al., 2011).
Alternative to ASH2L's function in H3K4 methylation
ASH2L may also be playing a role in endosomal
trafficking (Xu et al., 2009). ASH2L, DPY-30 and
WDR5 were originally implicated in endosomal
trafficking when siRNA knock-down of these genes
increased the amount of internalized CD8-CIMPR and
overexpression increased the amount of cells displaying
a altered CIMPR distribution (Xu et al., 2009).
Steward MM, Lee JS, O'Donovan A, Wyatt M, Bernstein BE,
Shilatifard A.. Molecular regulation of H3K4 trimethylation by
ASH2L, a shared subunit of MLL complexes. Nat Struct Mol
Biol. 2006 Sep;13(9):852-4. Epub 2006 Aug 6.
Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH.. Structural
and functional insights into the B30.2/SPRY domain. EMBO J.
2006a Mar 22;25(6):1353-63. Epub 2006 Feb 23.
Woo JS, Suh HY, Park SY, Oh BH.. Structural basis for protein
recognition by B30.2/SPRY domains. Mol Cell. 2006b Dec
28;24(6):967-76.
Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski
T, Dressler GR, Copeland TD, Kalkum M, Ge K.. PTIP
associates with MLL3- and MLL4-containing histone H3 lysine
4 methyltransferase complex. J Biol Chem. 2007 Jul
13;282(28):20395-406. Epub 2007 May 11.
Homology
ASH2L has homologs in eukaryotes from yeast to
humans.
Simonet T, Dulermo R, Schott S, Palladino F.. Antagonistic
functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans
development. Dev Biol. 2007 Dec 1;312(1):367-83. Epub 2007
Oct 29.
Implicated in
Various cancers
Note
ASH2L mRNA expression does not appear to be
misregulated in human cancer cell or primary cell lines.
However, expression of ASH2L protein is increased in
many cancer cell lines as well as tumor samples
(Lüscher-Firzlaff et al., 2008). There was detectable
increased staining in the nucleus of ASH2L protein in a
wide array of tumors including squamous cell
carcinoma of the larynx and the cervix, melanomas,
adenocarcinoma of the pancreas, and acinar and ductal
breast cancers (Lüscher-Firzlaff et al., 2008). ASH2L
protein appears to be more stable in cancer cell lines
compared to the normal cell line counterparts and
knockdown of ASH2L can prevent tumerogenesis
suggesting a role in tumor cell proliferation (LüscherFirzlaff et al., 2008).
Champagne KS, Saksouk N, Pena PV, Johnson K, Ullah M,
Yang XJ, Cote J, Kutateladze TG.. The crystal structure of the
ING5 PHD finger in complex with an H3K4me3 histone
peptide. Proteins. 2008 Sep;72(4):1371-6.
References
Kuang Z, Yao S, Xu Y, Lewis RS, Low A, Masters SL, Willson
TA, Kolesnik TB, Nicholson SE, Garrett TJ, Norton RS.. SPRY
domain-containing SOCS box protein 2: crystal structure and
residues critical for protein binding. J Mol Biol. 2009 Feb
27;386(3):662-74. Epub 2009 Jan 6.
Luscher-Firzlaff J, Gawlista I, Vervoorts J, Kapelle K,
Braunschweig T, Walsemann G, Rodgarkia-Schamberger C,
Schuchlautz H, Dreschers S, Kremmer E, Lilischkis R, Cerni C,
Wellmann A, Luscher B.. The human trithorax protein hASH2
functions as an oncoprotein. Cancer Res. 2008 Feb
1;68(3):749-58.
van Ingen H, van Schaik FM, Wienk H, Ballering J, Rehmann
H, Dechesne AC, Kruijzer JA, Liskamp RM, Timmers HT,
Boelens R.. Structural insight into the recognition of the
H3K4me3 mark by the TFIID subunit TAF3. Structure. 2008
Aug 6;16(8):1245-56.
Champagne KS, Kutateladze TG.. Structural insight into
histone recognition by the ING PHD fingers. Curr Drug
Targets. 2009 May;10(5):432-41. (REVIEW)
Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M,
Aasland R, Stewart AF. The Saccharomyces cerevisiae Set1
complex includes an Ash2 homologue and methylates histone
3 lysine 4. EMBO J. 2001 Dec 17;20(24):7137-48
Patel A, Dharmarajan V, Vought VE, Cosgrove MS.. On the
mechanism of multiple lysine methylation by the human mixed
lineage leukemia protein-1 (MLL1) core complex. J Biol Chem.
2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25.
Wang J, Zhou Y, Yin B, Du G, Huang X, Li G, Shen Y, Yuan J,
Qiang B. ASH2L: alternative splicing and downregulation
during induced megakaryocytic differentiation of multipotential
leukemia cell lines. J Mol Med (Berl). 2001 Jul;79(7):399-405
Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, Mu
D, Matsumoto B, Seaman M, Ma D.. A role of histone H3 lysine
4 methyltransferase components in endosomal trafficking. J
Cell Biol. 2009 Aug 10;186(3):343-53. Epub 2009 Aug 3.
Hess JL.. MLL: Deep Insight. Atlas Genet Cytogenet Oncol
Haematol. August 2003 .
Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD,
Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee
A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M..
Menin associates with a trithorax family histone
methyltransferase complex and with the hoxc8 locus. Mol Cell.
2004 Feb 27;13(4):587-97.
Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, Dou Y.. An
Ash2L/RbBP5
heterodimer
stimulates
the
MLL1
methyltransferase activity through coordinated substrate
interactions with the MLL1 SET domain. PLoS One. 2010 Nov
23;5(11):e14102.
Rhodes DA, de Bono B, Trowsdale J.. Relationship between
SPRY and B30.2 protein domains. Evolution of a component of
immune defence? Immunology. 2005 Dec;116(4):411-7.
(REVIEW)
Filippakopoulos P, Low A, Sharpe TD, Uppenberg J, Yao S,
Kuang Z, Savitsky P, Lewis RS, Nicholson SE, Norton RS,
Bullock AN.. Structural basis for Par-4 recognition by the SPRY
domain- and SOCS box-containing proteins SPSB1, SPSB2,
and SPSB4. J Mol Biol. 2010 Aug 20;401(3):389-402. Epub
2010 Jun 16.
Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL,
Allis CD, Roeder RG.. Regulation of MLL1 H3K4
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
32
ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila))
South PF, Briggs SD
South PF, Fingerman IM, Mersman DP, Du HN, Briggs SD.. A
conserved interaction between the SDI domain of Bre2 and the
Dpy-30 domain of Sdc1 is required for histone methylation and
gene expression. J Biol Chem. 2010 Jan 1;285(1):595-607.
Epub 2009 Nov 6.
Patel A, Vought VE, Dharmarajan V, Cosgrove MS.. A novel
non-SET domain multi-subunit methyltransferase required for
sequential nucleosomal histone H3 methylation by the mixed
lineage leukemia protein-1 (MLL1) core complex. J Biol Chem.
2011 Feb 4;286(5):3359-69. Epub 2010 Nov 24.
Stoller JZ, Huang L, Tan CC, Huang F, Zhou DD, Yang J, Gelb
BD, Epstein JA.. Ash2l interacts with Tbx1 and is required
during early embryogenesis. Exp Biol Med (Maywood). 2010
May;235(5):569-76.
Sarvan S, Avdic V, Tremblay V, Chaturvedi CP, Zhang P,
Lanouette S, Blais A, Brunzelle JS, Brand M, Couture JF..
Crystal structure of the trithorax group protein ASH2L reveals a
forkhead-like DNA binding domain. Nat Struct Mol Biol. 2011
Jun 5;18(7):857-9. doi: 10.1038/nsmb.2093.
Avdic V, Zhang P, Lanouette S, Groulx A, Tremblay V,
Brunzelle J, Couture JF.. Structural and biochemical insights
into MLL1 core complex assembly. Structure. 2011 Jan
12;19(1):101-8.
This article should be referenced as such:
South PF, Briggs SD. ASH2L (ash2 (absent, small, or
homeotic)-like (Drosophila)). Atlas Genet Cytogenet Oncol
Haematol. 2012; 16(1):30-33.
Chen Y, Wan B, Wang KC, Cao F, Yang Y, Protacio A, Dou Y,
Chang HY, Lei M.. Crystal structure of the N-terminal region of
human Ash2L shows a winged-helix motif involved in DNA
binding. EMBO Rep. 2011 Jun 10;12(8):797-803. doi:
10.1038/embor.2011.101.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
33
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
CD109 (CD109 molecule)
Shinji Mii, Yoshiki Murakumo, Masahide Takahashi
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan (SM,
YM, MT)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CD109ID42925ch6q13.html
DOI: 10.4267/2042/47266
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other
names:
CPAMD7,
DKFZp762L1111,
FLJ38569, FLJ41966, RP11-525G3.1
HGNC (Hugo): CD109
Location: 6q13
Note
CD109 is a glycosylphosphatidylinositol (GPI)anchored cell-surface glycoprotein and is a member of
the alpha-2-macroglobulin/C3,C4,C5 family of
thioester-containing proteins.
Description
CD109 is a GPI-anchored cell-surface glycoprotein and
is a member of the alpha-2-macroglobulin/C3,C4,C5
family of thioester-containing proteins (Sutherland et
al., 1991; Haregewoin et al., 1994; Smith et al., 1995;
Lin et al., 2002). The CD109 protein was first
identified as a cell-surface antigen detected by a
monoclonal antibody raised against the primitive
lymphoid/myeloid cell line KG1a (Sutherland et al.,
1991). It was also shown that CD109 carries the
biallelic platelet-specific alloantigen Gov (Kelton et al.,
1990; Smith et al., 1995).
DNA/RNA
Description
Expression
CD109 is a gene of 132.53 kb comprising 33 exons and
32 introns. The 5' part of exon 1 and the 3' part of exon
33 are non-coding.
CD109 is expressed on a subset of fetal and adult
CD34+ bone marrow mononuclear cells, mesenchymal
stem cell subsets, phytohemagglutinin (PHA)-activated
T lymphoblasts, thrombin-activated platelets, leukemic
megakaryoblasts, endothelial cells, and some human
tumor cell lines, but not on fresh peripheral leukocytes
and normal bone marrow leukocytes (Kelton et al.,
1990; Murray et al., 1999; Giesert et al., 2003).
Transcription
Three splice variants are known. The length of the
longest variant is 9464 bp (CDS: 426-4763). mRNA is
mainly expressed in skin and testis.
Pseudogene
Not known.
Exon-intron structure of CD109 gene. The vertical bars correspond to exons.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
34
CD109 (CD109 molecule)
Mii S, et al.
Representation of the CD109 protein with localization of recognized domains. CD109 protein is a GPI-anchored protein having signal
peptide, Gov antigen, thioester region, and furinase cleavage site.
In normal human tissues other than hematopoietic cells,
CD109 is expressed in limited cells including the
myoepithelial cells of the mammary, lacrimal, salivary
and bronchial glands and the basal cells of the prostate
and the bronchial epithelia (Hashimoto et al., 2004;
Zhang et al., 2005; Sato et al., 2007; Hasegawa et al.,
2007; Hasegawa et al., 2008).
Recently, it has been reported that CD109 is highly
expressed in several types of human cancer tissues, in
particular squamous cell carcinomas (Hashimoto et al.,
2004; Zhang et al., 2005; Sato et al., 2007; Hasegawa et
al., 2007; Hasegawa et al., 2008; Järvinen et al., 2008;
Hagiwara et al., 2008; Ohshima et al., 2010; Hagikura
et al., 2010).
urothelial carcinomas of the urinary bladder than in
moderately- or poorly-differentiated SCCs and in highgrade urothelial carcinomas, respectively (Hagiwara et
al., 2008; Hagikura et al., 2010).
Alloimmune thrombocytopenic
syndromes
Plasma membrane.
Note
Refractoriness to platelet transfusion, post-transfusion
purpura, and neonatal alloimmune thrombocytopenia
(Smith et al., 1995).
Disease
These diseases are included in alloimmune
platelet
thrombocytopenic
syndromes.
Gova/b
alloantigens, which reside in the CD109 protein, are the
cause of these 3 diseases.
Function
References
CD109 negatively regulates TGF-beta signaling in
keratinocytes by directly modulating TGF-beta receptor
activity in vitro (Finnson et al., 2006).
Kelton JG, Smith JW, Horsewood P, Humbert JR, Hayward
CP, Warkentin TE. Gova/b alloantigen system on human
platelets. Blood. 1990 Jun 1;75(11):2172-6
Localisation
Homology
Sutherland DR, Yeo E, Ryan A, Mills GB, Bailey D, Baker MA.
Identification of a cell-surface antigen associated with activated
T lymphoblasts and activated platelets. Blood. 1991 Jan
1;77(1):84-93
Orthologs: mouse CD109, rat CD109, cow CD109, dog
CD109, chicken CD109, hagfish CD109, nematode
CD109.
Paralogs:
alpha-2-macroglobulin,
alpha-2macroglobulin-like-1, C3, C4, C5, PZP, CPAMD8.
Haregewoin A, Solomon K, Hom RC, Soman G, Bergelson JM,
Bhan AK, Finberg RW. Cellular expression of a GPI-linked T
cell activation protein. Cell Immunol. 1994 Jul;156(2):357-70
Smith JW, Hayward CP, Horsewood P, Warkentin TE,
Denomme GA, Kelton JG. Characterization and localization of
the Gova/b alloantigens to the glycosylphosphatidylinositolanchored protein CDw109 on human platelets. Blood. 1995
Oct 1;86(7):2807-14
Mutations
Note
A Tyr703Ser polymorphism of CD109 is associated
with Gova and Govb alloantigenic determination (Schuh
et al., 2002).
Murray LJ, Bruno E, Uchida N, Hoffman R, Nayar R, Yeo EL,
Schuh AC, Sutherland DR. CD109 is expressed on a
subpopulation of CD34+ cells enriched in hematopoietic stem
and progenitor cells. Exp Hematol. 1999 Aug;27(8):1282-94
Implicated in
Lin M, Sutherland DR, Horsfall W, Totty N, Yeo E, Nayar R,
Wu XF, Schuh AC. Cell surface antigen CD109 is a novel
member of the alpha(2) macroglobulin/C3, C4, C5 family of
thioester-containing proteins. Blood. 2002 Mar 1;99(5):1683-91
Various cancer
Note
CD109 is upregulated in squamous cell carcinomas
(SCCs) of lung, esophagus, uterus and oral cavity,
malignant melanoma of skin, and urothelial carcinoma
of urinary bladder (Hashimoto et al., 2004; Zhang et
al., 2005; Sato et al., 2007; Hasegawa et al., 2007;
Hasegawa et al., 2008; Järvinen et al., 2008; Hagiwara
et al., 2008; Ohshima et al., 2010; Hagikura et al.,
2010).
Prognosis
The CD109 expression is significantly higher in welldifferentiated SCCs of the oral cavity and in low-grade
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Schuh AC, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper
JY, Campbell K, Sutherland DR, Metcalfe P, Horsfall W,
Ouwehand WH. A tyrosine703serine polymorphism of CD109
defines the Gov platelet alloantigens. Blood. 2002 Mar
1;99(5):1692-8
Giesert C, Marxer A, Sutherland DR, Schuh AC, Kanz L,
Buhring HJ. Antibody W7C5 defines a CD109 epitope
expressed on CD34+ and CD34- hematopoietic and
mesenchymal stem cell subsets. Ann N Y Acad Sci. 2003
May;996:227-30
Hashimoto M, Ichihara M, Watanabe T, Kawai K, Koshikawa K,
Yuasa N, Takahashi T, Yatabe Y, Murakumo Y, Zhang JM,
35
CD109 (CD109 molecule)
Mii S, et al.
Nimura Y, Takahashi M. Expression of CD109 in human
cancer. Oncogene. 2004 Apr 29;23(20):3716-20
Hagiwara S, Murakumo Y, Sato T, Shigetomi T, Mitsudo K,
Tohnai I, Ueda M, Takahashi M. Up-regulation of CD109
expression is associated with carcinogenesis of the squamous
epithelium of the oral cavity. Cancer Sci. 2008
Oct;99(10):1916-23
Zhang JM, Hashimoto M, Kawai K, Murakumo Y, Sato T,
Ichihara M, Nakamura S, Takahashi M. CD109 expression in
squamous cell carcinoma of the uterine cervix. Pathol Int. 2005
Apr;55(4):165-9
Järvinen AK, Autio R, Kilpinen S, Saarela M, Leivo I, Grénman
R, Mäkitie AA, Monni O. High-resolution copy number and
gene expression microarray analyses of head and neck
squamous cell carcinoma cell lines of tongue and larynx.
Genes Chromosomes Cancer. 2008 Jun;47(6):500-9
Finnson KW, Tam BY, Liu K, Marcoux A, Lepage P, Roy S,
Bizet AA, Philip A. Identification of CD109 as part of the TGFbeta receptor system in human keratinocytes. FASEB J. 2006
Jul;20(9):1525-7
Hagikura M, Murakumo Y, Hasegawa M, Jijiwa M, Hagiwara S,
Mii S, Hagikura S, Matsukawa Y, Yoshino Y, Hattori R, Wakai
K, Nakamura S, Gotoh M, Takahashi M. Correlation of
pathological grade and tumor stage of urothelial carcinomas
with CD109 expression. Pathol Int. 2010 Nov;60(11):735-43
Hasegawa M, Hagiwara S, Sato T, Jijiwa M, Murakumo Y,
Maeda M, Moritani S, Ichihara S, Takahashi M. CD109, a new
marker for myoepithelial cells of mammary, salivary, and
lacrimal glands and prostate basal cells. Pathol Int. 2007
May;57(5):245-50
Ohshima Y, Yajima I, Kumasaka MY, Yanagishita T, Watanabe
D, Takahashi M, Inoue Y, Ihn H, Matsumoto Y, Kato M. CD109
expression levels in malignant melanoma. J Dermatol Sci.
2010 Feb;57(2):140-2
Sato T, Murakumo Y, Hagiwara S, Jijiwa M, Suzuki C, Yatabe
Y, Takahashi M. High-level expression of CD109 is frequently
detected in lung squamous cell carcinomas. Pathol Int. 2007
Nov;57(11):719-24
This article should be referenced as such:
Hasegawa M, Moritani S, Murakumo Y, Sato T, Hagiwara S,
Suzuki C, Mii S, Jijiwa M, Enomoto A, Asai N, Ichihara S,
Takahashi M. CD109 expression in basal-like breast
carcinoma. Pathol Int. 2008 May;58(5):288-94
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Mii S, Murakumo Y, Takahashi M. CD109 (CD109 molecule).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):34-36.
36
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
CLDN7 (claudin 7)
Ana Carolina de Carvalho, Andre Vettore
Laboratory of Cancer Molecular Biology, Department of Biological Sciences, Federal University of Sao
Paulo, Diadema, SP, Brazil (ACd, AV)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CLDN7ID40099ch17p13.html
DOI: 10.4267/2042/47267
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
Other names: CEPTRL2,
Hs.84359, claudin-1
HGNC (Hugo): CLDN7
Location: 17p13.1
CLDN-7,
This gene contains 4 exons and 3 introns. The
transcription produces 3 alternatively spliced mRNA
variants:
- variant 1 (NM_001307.5) encodes the longer isoform;
- variant 2 (NM_001185022.1) has an alternate 5' UTR
sequence;
- variant 3 (NM_001185023.1) lacks an exon in the 3'
CDS.
CPETRL2,
DNA/RNA
Description
Pseudogene
2573 base-pairs, starts at 7163223 and ends at 7165795
bp from pter with minus strand orientation.
The sequence named LOC100129851 claudin 7
pseudogene is a pseudogene of Claudin 7 located at
Xp11.4.
Figure 1. Schematic representation of the claudin 7 chromosome location, transcript variants and protein isoforms.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
37
CLDN7 (claudin 7)
de Carvalho AC, Vettore A
Figure 2. Schematic representation of the claudin 7 protein showing the extracellular loops (EL1 and EL2), the transmembrane domains
(TM1 to TM4) and its amino- and carboxy-terminal tails extending into the cytoplasm.
VATMGMKCTRCGGDDKVKKARIAMGGGIIFIVA
GMSLALPSLLAGQGLP
Protein
Description
CLDN-7 is an integral membrane protein with four
hydrophobic transmembrane domains and two
extracellular loops which appear to be implicated in
tight junction formation and with their amino- and
carboxy-terminal tails extending into the cytoplasm
(figure 2).
The transcription of this gene gives 3 alternatively
spliced mRNA variants that encode 2 different protein
isoforms (variants 1 and 2 encode the same isoform):
- Isoform 1 is the canonical sequence with 211 amino
acids and it weighs 22418 Da.
MANSGLQLLGFSMALLGWVGLVACTAIPQWQM
SSYAGDNIITAQAMYKGLWMDCVTQSTGMMSC
KMYDSVLALSAALQATRALMVVSLVLGFLAMF
VATMGMKCTRCGGDDKVKKARIAMGGGIIFIVA
GLAALVACSWYGHQIVTDFYNPLIPTNIKYEFGP
AIFIGWAGSALVILGGALLSCSCPGNESKAGYRV
PRSYPKSNSSKEYV
Localisation
The protein is localized in the cell membrane as a
constituent of tight junctions.
Function
CLDN-7 encodes a member of the claudin family of
integral transmembrane proteins that are components of
tight junction strands. Claudins regulate the
paracellular transport being essential in maintaining a
functional epithelial barrier, and also play critical roles
in maintaining cell polarity and signal transductions.
Studies have shown that altered levels of the different
claudins may be related to invasion and progression of
carcinoma cells in several primary neoplasms.
- Isoform 2 contains 145 amino acids, with a shorter Cterminus, lacking amino acids 159 to 211 in
comparison to isoform 1. It weighs 15156 Da.
MANSGLQLLGFSMALLGWVGLVACTAIPQWQM
SSYAGDNIITAQAMYKGLWMDCVTQSTGMMSC
KMYDSVLALSAALQATRALMVVSLVLGFLAMF
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
38
CLDN7 (claudin 7)
de Carvalho AC, Vettore A
Esophageal cancer
Mutations
Prognosis
Usami et al. (2006) found that reduced expression of
Claudin 7 at the invasive front of the esophageal cancer
was significantly associated with the depth of invasion,
lymphatic vessel invasion, and lymph node metastasis.
Reduced Claudin 7 expression was also found in the
metastatic lymph nodes. They suggest that the reduced
expression of Claudin 7 at the invasive front of
esophageal squamous cell carcinoma may lead to tumor
progression and subsequent metastatic events.
Somatic
In the catalogue of Somatic Mutations in Cancer
(Sanger) reports only a heterozygous silent substitution
(339G/T;
V113V)
in
ovarian
serous
cystadenocarcinoma is present.
Polymorphisms
According to the Ensembl database 12 variations could
be present in the transcripts (variants 1/2) of CLDN-7:
Position 963/396 of mRNA a synonymous G/A
polymorphism at position 61 of the amino acid
sequence.
Position 979/412 of mRNA a non-synonymous G/T
polymorphism at position 77 of the amino acid
sequence. Switching an Ala for an Asp residue. SIFT
deleterious.
Position 1299/732 of mRNA a non-synonymous C/T
polymorphism at position 397 of the amino acid
sequence. Switching an Ala for an Thr residue. SIFT
tolerated.
Position 1425/858 of mRNA a non-synonymous C/A
polymorphism at position 523 of the amino acid
sequence. Switching an Val for an Phe residue. SIFT
deleterious.
Position 1492/925 of mRNA a non-synonymous A/G
polymorphism at position 590 of the amino acid
sequence. Switching an Val for an Ala residue. SIFT
tolerated.
Position 1508/941 of mRNA a synonymous A/C
polymorphism at position 606 of the amino acid
sequence.
Epithelial ovarian carcinoma
Prognosis
Kim et al. (2011) described the up-regulation of
Claudin 7 transcripts in patients with epithelial ovarian
carcinoma (EOCs) in comparison to normal ovarian
tissues. The protein Claudin 7 was observed in the
majority of the EOCs but not in normal ovarian tissues.
High Claudin 7 expression in primary tumor correlated
with shorter progression-free survival and poor
sensitivity to platinum-based chemotherapy. Claudin 7
inhibition in 2774 and HeyA8 human ovarian cancer
cells by siRNA significantly enhanced the sensitivity of
these cells to cisplatin treatment. These findings
suggest Claudin 7 expression as an independent
prognostic factor for progression-free survival in EOCs
patients and that it may play a role in regulating
response to platinum-based chemotherapy in the
treatment of these tumors.
Oncogenesis
Tassi et al. (2008) found Claudin 7 transcript and
protein significantly overexpressed in both primary and
metastatic EOCs compared to normal ovaries.
Moreover, a strong immunoreactivity for Claudin 7 was
detected in EOC cells present in ascites fluids, whereas
ascites-derived inflammatory cells, histiocytes, and
reactive mesothelial cells were negative. Claudin 7 is
significantly overexpressed in all main histologic types
of EOC and in single neoplastic cells disseminated in
peritoneal cavity and pleural effusions, suggesting its
potential role as novel diagnostic marker in ovarian
cancer.
Implicated in
Colorectal carcinoma
Prognosis
Oshima et al. (2008) studied surgical specimens of
cancer tissue and adjacent normal mucosa from patients
with untreated colorectal carcinoma. The reduced
expression of Claudin 7 correlated with venous
invasion and liver metastasis, thus suggesting that the
reduced expression of the Claudin 7 gene may be a
useful predictor of liver metastasis in patients with
colorectal cancer.
Oncogenesis
Bornholdt et al. (2011) observed that Claudin 7 gene
was downregulated both at mRNA and protein levels in
biopsies of colorectal tissue from mild/moderate
dysplasia, severe dysplasia and carcinomas when
comparing to biopsies from healthy individuals. These
results suggest that Claudin 7 downregulation is as an
early event in colorectal carcinogenesis, probably
contributing to the compromised epithelial barrier in
adenomas.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Prostatic carcinoma
Prognosis
Sheehan et al. (2007) reported the pattern of claudin
expression in prostatic adenocarcinomas (PACs) and
found that the decreased expression of Claudin 7 was
correlated with high tumor grade.
Oral squamous cell carcinoma
Prognosis
Lourenço et al. (2010) showed that Claudin 7
expression was mostly negative or weakly expressed in
oral squamous cell carcinoma samples. According their
39
CLDN7 (claudin 7)
de Carvalho AC, Vettore A
both ductal carcinoma in situ and invasive ductal carcinoma of
the breast. Oncogene. 2003 Apr 3;22(13):2021-33
results, the loss of Claudin 7 expression was associated
with tumor size, clinical stage and a worse disease-free
survival.
Lee JW, Lee SJ, Seo J, Song SY, Ahn G, Park CS, Lee JH,
Kim BG, Bae DS. Increased expressions of claudin-1 and
claudin-7 during the progression of cervical neoplasia. Gynecol
Oncol. 2005 Apr;97(1):53-9
Uterine cervical neoplasia
Oncogenesis
Lee et al. (2005) showed that Claudin 7 expressions is
associated with the progression of uterine cervical
neoplasia since its expression was undetectable in
normal cervical squamous epithelium and gradually
increase in accordance with the progression from LSIL
(low-grade squamous intraepithelial lesion) to HSIL
(high-grade squamous intraepithelial lesion) and ISCC
(invasive squamous cell carcinoma). Claudin 7 were
detected in all cases of ISCC. These authors suggested
that Claudin 7 may play a significant role in tumor
progression of cervical neoplasia.
Sauer T, Pedersen MK, Ebeltoft K, Naess O. Reduced
expression of Claudin-7 in fine needle aspirates from breast
carcinomas correlate with grading and metastatic disease.
Cytopathology. 2005 Aug;16(4):193-8
Usami Y, Chiba H, Nakayama F, Ueda J, Matsuda Y, Sawada
N, Komori T, Ito A, Yokozaki H. Reduced expression of
claudin-7 correlates with invasion and metastasis in squamous
cell carcinoma of the esophagus. Hum Pathol. 2006
May;37(5):569-77
Sheehan GM, Kallakury BV, Sheehan CE, Fisher HA, Kaufman
RP Jr, Ross JS. Loss of claudins-1 and -7 and expression of
claudins-3 and -4 correlate with prognostic variables in
prostatic adenocarcinomas. Hum Pathol. 2007 Apr;38(4):564-9
Breast cancer
Oshima T, Kunisaki C, Yoshihara K, Yamada R, Yamamoto N,
Sato T, Makino H, Yamagishi S, Nagano Y, Fujii S, Shiozawa
M, Akaike M, Wada N, Rino Y, Masuda M, Tanaka K, Imada T.
Reduced expression of the claudin-7 gene correlates with
venous invasion and liver metastasis in colorectal cancer.
Oncol Rep. 2008 Apr;19(4):953-9
Prognosis
Kominsky et al. (2003) conducted RT-PCR and
Western Blot analysis and reported that Claudin 7
expression is lower in breast invasive ductal
carcinomas (IDC) than in normal breast epithelium.
They also reported immunohistochemical (IHC)
analysis of ductal carcinoma in situ (DCIS) and IDC
and showed that the loss of Claudin 7 expression is
correlated with histological grade, occurring
predominantly in high-grade lesions. According to their
results, Claudin 7 expression was lost in the vast
majority of in situ lobular carcinoma cases. In
summary, this study provides insight into the potential
role of Claudin 7 in the breast tumor progression and in
the ability of breast cancer cells to disseminate.
Sauer et al. (2005) evaluated the immunocytochemical
expression of Claudin 7 in fine needle aspirates of
breast carcinomas and found that reduced Claudin 7
expression was correlated with grading, locoregional
and distant metastases, nodal involvement and cellular
cohesion in invasive carcinomas.
Tassi RA, Bignotti E, Falchetti M, Ravanini M, Calza S,
Ravaggi A, Bandiera E, Facchetti F, Pecorelli S, Santin AD.
Claudin-7 expression in human epithelial ovarian cancer. Int J
Gynecol Cancer. 2008 Nov-Dec;18(6):1262-71
Lourenço SV, Coutinho-Camillo CM, Buim ME, de Carvalho
AC, Lessa RC, Pereira CM, Vettore AL, Carvalho AL, Fregnani
JH, Kowalski LP, Soares FA. Claudin-7 down-regulation is an
important feature in oral squamous cell carcinoma.
Histopathology. 2010 Nov;57(5):689-98
Bornholdt J, Friis S, Godiksen S, Poulsen SS, Santoni-Rugiu
E, Bisgaard HC, Lothe IM, Ikdahl T, Tveit KM, Johnson E, Kure
EH, Vogel LK. The level of claudin-7 is reduced as an early
event in colorectal carcinogenesis. BMC Cancer. 2011 Feb
10;11:65
Kim CJ, Lee JW, Choi JJ, Choi HY, Park YA, Jeon HK, Sung
CO, Song SY, Lee YY, Choi CH, Kim TJ, Lee JH, Kim BG, Bae
DS. High claudin-7 expression is associated with a poor
response to platinum-based chemotherapy in epithelial ovarian
carcinoma. Eur J Cancer. 2011 Apr;47(6):918-25
References
This article should be referenced as such:
de Carvalho AC, Vettore A. CLDN7 (claudin 7). Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(1):37-40.
Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E,
Rein A, Sauter G, Kallioniemi OP, Sukumar S. Loss of the tight
junction protein claudin-7 correlates with histological grade in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
40
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
CSE1L (CSE1 chromosome segregation 1-like
(yeast))
Ming-Chung Jiang
Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University
Hospital, Taipei, Taiwan (MCJ)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CSE1LID40159ch20q13.html
DOI: 10.4267/2042/47268
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Description
Identity
Other
names:
CAS,
CSE1,
MGC130036, MGC130037, XPO2
HGNC (Hugo): CSE1L
Location: 20q13.13
CSE1L gene encodes a 971-amino acid protein with an
approximately 100-kDa molecular mass (Brinkmann et
al., 1995).
MGC117283,
Expression
Multiple transcript variants encoding several different
isoforms in a tissue-specific manner have been
described for CSE1L gene (Brinkmann et al., 1999).
CSE1L is expressed in various tissues, and particularly
it is highly expressed in most cancer (Tai et al., 2010a;
Brinkmann et al., 1995). The expression level CSE1L
is positively correlated with high tumor stage, high
tumor grade, and worse outcomes of cancer patients
(Tai et al., 2010a). The increased expression of CSE1L
in cancer is mainly due to the amplification of the copy
number of the CSE1L gene in cancer tissue (Tai et al.,
2010a). The association of CSE1L with microtubules is
related with pseudopodia extension and the migration
of cancer cells (Tai et al., 2010b). CSE1L is also a
secretory protein, and it is present is the sera of cancer
patients. The secretion of CSE1L is related with the
invasion of cancer cells (Tung et al., 2009; Stella Tsai
et al., 2010).
Protein
Localisation
DNA/RNA
Note
CDS: 2915 bp.
Description
The CSE1L gene consists of 25 exons (Brinkmann et
al., 1999). The CSE1L gene is high-frequency
amplified in various cancer types (Tai et al., 2010a).
Transcription
Nucleus, cytoplasm.
Note
CSE1L is a multiple function protein. The protein is
involved in nuclear protein transport (Lindsay et al.,
2002), cell apoptosis (Brinkmann et al., 1996),
microtubule assembly (Scherf et al., 1996), cell
secretion (Tsao et al., 2009), and cancer cell invasion
(Liao et al., 2008; Tung et al., 2009; Stella Tsai et al.,
2010) etc.
Function
A cell apoptosis susceptibility protein; a microtubuleassociated protein; an export receptor of importin-a in
the nuclear protein import cycle; involved in tumor cell
invasion and metastasis in cancer progression.
Homology
The yeast chromosome segregation gene CSE1.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
41
CSE1L (CSE1 chromosome segregation 1-like (yeast))
Jiang MC
In contrast, highly malignant non-Hodgkin's lymphoma
and malignant cells of Hodgkin's disease displayed
very strong CSE1L positivity, with staining of up to
80% of atypical cells (Wellmann et al., 1997).
Implicated in
Breast cancer
Prognosis
Benign breast lesions show weak cytoplasmatic CSE1L
staining, while in ductal and lobular in situ carcinomas,
70%-90% of breast tumor cells showed heavy CSE1L
staining cytoplasm. Also, in invasive ductal and lobular
carcinomas, 70-90% of the tumor cells showed heavy
CSE1L staining pattern predominantly in nuclei
(Behrens et al., 2001).
Endometrial carcinomas
Prognosis
An analysis of 89 endometrial carcinomas and 56
samples of non-neoplastic adjacent endometrium
showed that CSE1L was expressed in 93% of
endometrial carcinomas neoplastic tissues, while lower
levels of CSE1L expression were observed in the
adjacent endometrium compared to the carcinomas (p =
0.003). Also, CSE1L expression was higher in grade 3
tumors (p = 0.002) (Peiró et al., 2001).
Ovarian carcinoma
Prognosis
In serous ovarian carcinoma, moderate to strong
immunostaining of CSE1L was observed in 34 of 41
cases (83%) of serous carcinomas, and CSE1L
immunoreactivity was positively related to the
frequency of apoptotic bodies (p = 0.0170), the tumor
grade (p = 0.0107), and adverse outcomes (p = 0.0035).
CSE1L protein reactivity was present in 100% of 69
ovarian carcinomas, and a significant reciprocal
correlation was observed between high levels of
CSE1L and the histological type, FIGO (International
Federation of Obstetrics and Gynecology) stage III and
grade 3, residual tumors of > 2 cm, and 20q13.2
(ZNF217 gene) amplification (> four copies in > 20%
cells). A tissue array study composed of 244 serous
ovarian tumors of different grades (0-3) and stages (IIV) showed a higher expression of CSE1L in poorly
compared to highly differentiated invasive ovarian
tumors (Brustmann, 2004; Peiro et al., 2002; Ouellet et
al., 2006).
Hepatocellular carcinomas
Prognosis
The expression of CSE1L was not detected in normal
hepatocytes, while strong CSE1L expression was
detected in hepatocellular carcinoma. Study also
showed that the immunohistochemical staining
intensity score of CSE1L was significantly higher in
human hepatocellular carcinoma than in non-tumor
tissue (p < 0.05) (Wellmann et al., 2001; Shiraki et al.,
2006).
Lung cancer
Prognosis
The immunophenotypic profiling of non-small cell lung
cancer progression using tissue microarray with 59
tissue samples, including 33 primary tumors without
distant metastasis and 26 non-small cell lung cancer
with brain metastases and showed that elevated
expression of CSE1L was significantly associated with
the metastatic potential of non-small cell lung cancer
(Papay et al., 2007).
Melanomas
Prognosis
Analysis of the expression of CSE1L in 27 control
benign and 55 malignant melanocytic lesions
(including 32 primary and 23 metastatic lesions), and
the results showed that only 13 of the 27 benign
melanocytic lesions stained positive for CSE1L.
However, 5 of 7 lentigo maligna melanomas, 11 of 12
superficial
spreading
melanomas,
and
all
acrolentiginous (n = 7) and nodular (n = 6) melanomas
showed medium to high intensity immunoreactivity for
CSE1L staining. All metastatic melanomas (n = 23)
showed strong CSE1L staining. Also, CSE1L detection
in clinical stages according to the International Union
Against Cancer (UICC) showed an increase from 43%
± 34% CSEL-positive cells in stage I, to 53% ± 26% in
stage II, 68% ± 24% in stage III, and 72% ± 24% in
stage IV (Böni et al., 1999).
Gliomas
Prognosis
The results of array-based comparative genomic
hybridization showed that 57.1% of the glioblastoma
multiforme cases had high-frequency amplification of
the CSE1L gene. Idbaih et al. investigated a series of
16 low-grade gliomas and their subsequent progression
to higher-grade malignancies using a one-megabase
bacterial artificial chromosome (BAC)-based array
comparative genomic hybridization technique, and
reported that the CSE1L gene was associated with the
progression of gliomas (Hui et al., 2001; Idbaih et al.,
2008).
Colorectal carcinoma
Prognosis
The expression of CSE1L was also reported to be
higher in the primary and metastatic human colorectal
carcinoma compared to the normal colon mucosa (p <
0.0001). Also, the concentration of CSE1L in serum is
positively correlated with the stage of colorectal cancer
(Stella Tsai et al., 2010; Seiden-Long et al., 2006).
Lymphomas
Prognosis
In normal lymphoid tissue and malignant lymphomas,
low-grade non-Hodgkin's lymphoma revealed weak
CSE1L staining, with 10% to 60% of all cells positive.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
42
CSE1L (CSE1 chromosome segregation 1-like (yeast))
Jiang MC
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Seiden-Long IM, Brown KR, Shih W, Wigle DA, Radulovich N,
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apoptosis-associated CAS protein in lymphoid neoplasms. Am
J Pathol. 1997 Jan;150(1):25-30
Papay J, Krenacs T, Moldvay J, Stelkovics E, Furak J, Molnar
B, Kopper L. Immunophenotypic profiling of nonsmall cell lung
cancer progression using the tissue microarray approach. Appl
Immunohistochem Mol Morphol. 2007 Mar;15(1):19-30
Böni R, Wellmann A, Man YG, Hofbauer G, Brinkmann U.
Expression of the proliferation and apoptosis-associated CAS
protein in benign and malignant cutaneous melanocytic
lesions. Am J Dermatopathol. 1999 Apr;21(2):125-8
Idbaih A, Carvalho Silva R, Crinière E, Marie Y, Carpentier C,
Boisselier B, Taillibert S, Rousseau A, Mokhtari K, Ducray F,
Thillet J, Sanson M, Hoang-Xuan K, Delattre JY. Genomic
changes in progression of low-grade gliomas. J Neurooncol.
2008 Nov;90(2):133-40
Brinkmann U, Brinkmann E, Bera TK, Wellmann A, Pastan I.
Tissue-specific alternative splicing of the CSE1L/CAS (cellular
apoptosis susceptibility) gene. Genomics. 1999 May
15;58(1):41-9
Liao CF, Luo SF, Li LT, Lin CY, Chen YC, Jiang MC.
CSE1L/CAS, the cellular apoptosis susceptibility protein,
enhances invasion and metastasis but not proliferation of
cancer cells. J Exp Clin Cancer Res. 2008 Jul 3;27:15
Behrens P, Brinkmann U, Fogt F, Wernert N, Wellmann A.
Implication of the proliferation and apoptosis associated
CSE1L/CAS gene for breast cancer development. Anticancer
Res. 2001 Jul-Aug;21(4A):2413-7
Tung MC, Tsai CS, Tung JN, Tsao TY, Chen HC, Yeh KT, Liao
CF, Jiang MC. Higher prevalence of secretory CSE1L/CAS in
sera of patients with metastatic cancer. Cancer Epidemiol
Biomarkers Prev. 2009 May;18(5):1570-7
Hui AB, Lo KW, Yin XL, Poon WS, Ng HK. Detection of
multiple gene amplifications in glioblastoma multiforme using
array-based comparative genomic hybridization. Lab Invest.
2001 May;81(5):717-23
Tsao TY, Tsai CS, Tung JN, Chen SL, Yue CH, Liao CF, Wang
CC, Jiang MC. Function of CSE1L/CAS in the secretion of HT29 human colorectal cells and its expression in human colon.
Mol Cell Biochem. 2009 Jul;327(1-2):163-70
Peiró G, Diebold J, Baretton GB, Kimmig R, Löhrs U. Cellular
apoptosis susceptibility gene expression in endometrial
carcinoma: correlation with Bcl-2, Bax, and caspase-3
expression and outcome. Int J Gynecol Pathol. 2001
Oct;20(4):359-67
Stella Tsai CS, Chen HC, Tung JN, Tsou SS, Tsao TY, Liao
CF, Chen YC, Yeh CY, Yeh KT, Jiang MC. Serum cellular
apoptosis susceptibility protein is a potential prognostic marker
for metastatic colorectal cancer. Am J Pathol. 2010
Apr;176(4):1619-28
Wellmann A, Flemming P, Behrens P, Wuppermann K, Lang
H, Oldhafer K, Pastan I, Brinkmann U. High expression of the
proliferation and apoptosis associated CSE1L/CAS gene in
hepatitis and liver neoplasms: correlation with tumor
progression. Int J Mol Med. 2001 May;7(5):489-94
Tai CJ, Hsu CH, Shen SC, Lee WR, Jiang MC. Cellular
apoptosis susceptibility (CSE1L/CAS) protein in cancer
metastasis and chemotherapeutic drug-induced apoptosis. J
Exp Clin Cancer Res. 2010a Aug 11;29:110
Lindsay ME, Plafker K, Smith AE, Clurman BE, Macara IG.
Npap60/Nup50 is a tri-stable switch that stimulates importinalpha:beta-mediated nuclear protein import. Cell. 2002 Aug
9;110(3):349-60
Tai CJ, Shen SC, Lee WR, Liao CF, Deng WP, Chiou HY,
Hsieh CI, Tung JN, Chen CS, Chiou JF, Li LT, Lin CY, Hsu
CH, Jiang MC. Increased cellular apoptosis susceptibility
(CSE1L/CAS) protein expression promotes protrusion
extension and enhances migration of MCF-7 breast cancer
cells. Exp Cell Res. 2010b Oct 15;316(17):2969-81
Peiró G, Diebold J, Löhrs U. CAS (cellular apoptosis
susceptibility) gene expression in ovarian carcinoma:
Correlation with 20q13.2 copy number and cyclin D1, p53, and
Rb protein expression. Am J Clin Pathol. 2002 Dec;118(6):9229
This article should be referenced as such:
Jiang MC. CSE1L (CSE1 chromosome segregation 1-like
(yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012;
16(1):41-43.
Brustmann H. Expression of cellular apoptosis susceptibility
protein in serous ovarian carcinoma: a clinicopathologic and
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
43
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5)
Zhi-Ren Liu
Departments of Biology, Georgia State University, Atlanta, GA 30303, USA (ZRL)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/DDX5ID40290ch17q23.html
DOI: 10.4267/2042/47269
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Yang et al., 2006), pre-rRNA processing (Jalal et al.,
2007), pre-miRNA processing (Fukuda et al., 2007),
DNA methylation and de-methylation (Jost et al.,
1999), and chromatin remodeling (Carter et al., 2010).
A number of different post-translational modifications
of p68 are reported, including phosphorylations,
sumoylation, and ubiquitylation (Causevic et al., 2001;
Yang et al., 2005; Jacobs et al., 2007).
Identity
Other names: DKFZp434E109,
DKFZp686J01190, G17P1, HLR1, HUMP68, p68
HGNC (Hugo): DDX5
Location: 17q23.3
Note
DDX5/p68 RNA helicase is a member of DEAD box
RNA helicases. As an example of a cellular RNA
helicase, the ATPase and the RNA unwinding activities
of p68 RNA helicase were documented with the protein
that was purified from human 293 cells (Iggo and Lane,
1989; Ford et al.,1988; Hirling et al., 1989) and
recombinant protein expressed in E. coli (Huang and
Liu, 2002). The gene is expressed in all dividing cells
of different vertebrates (Lane and Hoeffler, 1980;
Stevenson et al., 1998). p68 RNA helicase is involved
in multiple cellular processes, including gene
transcription (Endoh et al., 1999; Rossow and
Janknecht, 2003), pre-mRNA processing (Liu, 2002;
DNA/RNA
Note
DDX5/p68 RNA helicase is expressed in dividing cells
of different vertebrates. Transcription of p68 RNA
helicase gene generates a single mRNA precusor with
13 exons and 12 introns. Alternative splicing produces
two mRNA transcripts, 2.3 kb and 4.4 kb (Rössler et
al., 2000). The 2.3 kb mRNA transcript codes full
length p68, while no translational product from the 4.4
kb mRNA transcript is detected in cellular and tissue
extracts (Rössler et al., 2000).
Diagram of pre-mRNA of p68 RNA helicase. The red bars are exons and the blue thin lines are introns.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
44
DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5)
Liu ZR
Domain structure of p68 RNA helicase. Functional sequence motifs are marked.
Epithelial-Mesenchymal-Transition
(EMT).p68
becomes phosphorylated at Y593 upon growth factor
stimulation by c-Abl. The tyrosine phosphorylation of
p68 mediates growth factor stimulated EpithelialMesenchymal-Transition (EMT) (Yang et al., 2006).
Other functions. (1) p68 RNA helicase is shown to
unwind the human let-7 microRNA precursor duplex.
The protein is required for let-7-directed silencing of
gene expression (Salzman et al., 2007). p68 is an
indispensible part of Drosha complex. Its activity is
required for primary miRNA and rRNA processing
(Fukuda et al., 2007). (2) It is also demonstrated that
the RNA helicases p68/p72 and the noncoding RNA
SRA are coregulators of MyoD and skeletal muscle
differentiation
(Caretti
et
al.,
2006).
(3)
Phosphorylation of p68 at Thr residues mediates cell
apoptosis (Yang et al., 2007).
Protein
Description
Size of p68; 614 amino acids, 69 kDa.
Expression
Expressed in almost all tissue types. Its expression is
increased in cancer cells.
Localisation
Dominately localized in the cell nucleus. It is also
found in the cytoplasm in various physiological
conditions. p68 is a nucleocytoplasm shuttling protein
(Wang et al., 2009).
Function
Pre-mRNA splicing.The protein was demonstrated to
associate with spliceosome by mass-spectroscopy and
an RNA-protein crosslinking analyses (Hartmuth et al.,
2002; Liu et al., 1997; Neubauer et al., 1998). p68 is
functionally involved in assemble of the splicesome by
mediating the U1 snRNP and the 5'ss interaction (Liu,
2002). p68 RNA helicase is also shown to regulate the
splice site selection in the alternative splicing of several
growth related genes, such as c-H-ras and tau (Kar et
al., 2011; Guil et al., 2003).
Transcriptional regulation.The protein is shown to
involve in transcriptional regulation by different
mechanism of actions dependent on each individual
regulated gene and biological processes (Stevenson et
al., 1998; Endoh et al., 1999; Yang et al., 2005; Kahlina
et al., 2004; Wei and Hu, 2001; Warner et al., 2004).
p68 may regulate gene transcription by direct
interaction with transcription factors or activators, such
as p53, ERalpha (Endoh et al., 1999; Bates et al.,
2005), or by mediating chromatin remodeling, such as
modulating chromatin remodeling complex (Carter et
al., 2010).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Homology
Yeast DBP2.
Mutations
Note
Very few mutations of p68 gene were reported. A
recent study shows that a S480A mutation in hepatic
stellate cells is associated with hepatic fibrosis (Guo et
al., 2010).
Implicated in
Colon cancer
Note
p68 expression is significantly increased in colon
cancer (Shin et al., 2007). Phosphorylation of p68 at
Tyr correlation with colon cancer metastasis (Yang et
al., 2006; Yang et al., 2005).
45
DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5)
Liu ZR
ras alternative splicing regulation. Mol Cell Biol. 2003
Apr;23(8):2927-41
Prognosis
Phosphorylation of p68 at tyrosine can be used as a
diagnosis/prognosis marker for cancer.
Rossow KL, Janknecht R. Synergism between p68 RNA
helicase and the transcriptional coactivators CBP and p300.
Oncogene. 2003 Jan 9;22(1):151-6
References
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RNA helicase expression in keratinocytes. Regulation,
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Lane DP, Hoeffler WK. SV40 large T shares an antigenic
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Nature. 1980 Nov 13;288(5787):167-70
Ford MJ, Anton IA, Lane DP. Nuclear protein with sequence
homology to translation initiation factor eIF-4A. Nature. 1988
Apr 21;332(6166):736-8
Warner DR, Bhattacherjee V, Yin X, Singh S, Mukhopadhyay
P, Pisano MM, Greene RM. Functional interaction between
Smad, CREB binding protein, and p68 RNA helicase. Biochem
Biophys Res Commun. 2004 Nov 5;324(1):70-6
Hirling H, Scheffner M, Restle T, Stahl H. RNA helicase activity
associated with the human p68 protein. Nature. 1989 Jun
15;339(6225):562-4
Bates GJ, Nicol SM, Wilson BJ, Jacobs AM, Bourdon JC,
Wardrop J, Gregory DJ, Lane DP, Perkins ND, Fuller-Pace FV.
The DEAD box protein p68: a novel transcriptional coactivator
of the p53 tumour suppressor. EMBO J. 2005 Feb 9;24(3):54353
Iggo RD, Lane DP. Nuclear protein p68 is an RNA-dependent
ATPase. EMBO J. 1989 Jun;8(6):1827-31
Liu ZR, Laggerbauer B, Lührmann R, Smith CW. Crosslinking
of the U5 snRNP-specific 116-kDa protein to RNA hairpins that
block step 2 of splicing. RNA. 1997 Nov;3(11):1207-19
Yang L, Lin C, Liu ZR. Phosphorylations of DEAD box p68
RNA helicase are associated with cancer development and cell
proliferation. Mol Cancer Res. 2005 Jun;3(6):355-63
Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh
P, Sleeman J, Lamond A, Mann M. Mass spectrometry and
EST-database searching allows characterization of the multiprotein spliceosome complex. Nat Genet. 1998 Sep;20(1):4650
Stevenson RJ, Hamilton SJ, MacCallum DE,
Pace FV. Expression of the 'dead box' RNA
developmentally and growth regulated and
organ differentiation/maturation in the fetus.
Apr;184(4):351-9
Caretti G, Schiltz RL, Dilworth FJ, Di Padova M, Zhao P,
Ogryzko V, Fuller-Pace FV, Hoffman EP, Tapscott SJ,
Sartorelli V. The RNA helicases p68/p72 and the noncoding
RNA SRA are coregulators of MyoD and skeletal muscle
differentiation. Dev Cell. 2006 Oct;11(4):547-60
Hall PA, Fullerhelicase p68 is
correlates with
J Pathol. 1998
Yang L, Lin C, Liu ZR. P68 RNA helicase mediates PDGFinduced epithelial mesenchymal transition by displacing Axin
from beta-catenin. Cell. 2006 Oct 6;127(1):139-55
Fukuda T, Yamagata K, Fujiyama S, Matsumoto T, Koshida I,
Yoshimura K, Mihara M, Naitou M, Endoh H, Nakamura T,
Akimoto C, Yamamoto Y, Katagiri T, Foulds C, Takezawa S,
Kitagawa H, Takeyama K, O'Malley BW, Kato S. DEAD-box
RNA helicase subunits of the Drosha complex are required for
processing of rRNA and a subset of microRNAs. Nat Cell Biol.
2007 May;9(5):604-11
Endoh H, Maruyama K, Masuhiro Y, Kobayashi Y, Goto M, Tai
H, Yanagisawa J, Metzger D, Hashimoto S, Kato S.
Purification and identification of p68 RNA helicase acting as a
transcriptional coactivator specific for the activation function 1
of human estrogen receptor alpha. Mol Cell Biol. 1999
Aug;19(8):5363-72
Jost JP, Schwarz S, Hess D, Angliker H, Fuller-Pace FV, Stahl
H, Thiry S, Siegmann M. A chicken embryo protein related to
the mammalian DEAD box protein p68 is tightly associated
with the highly purified protein-RNA complex of 5-MeC-DNA
glycosylase. Nucleic Acids Res. 1999 Aug 15;27(16):3245-52
Jacobs AM, Nicol SM, Hislop RG, Jaffray EG, Hay RT, FullerPace FV.. SUMO modification of the DEAD box protein p68
modulates its transcriptional activity and promotes its
interaction with HDAC1. Oncogene. 2007 Aug 30;26(40):586676. Epub 2007 Mar 19.
Rössler OG, Hloch P, Schütz N, Weitzenegger T, Stahl H.
Structure and expression of the human p68 RNA helicase
gene. Nucleic Acids Res. 2000 Feb 15;28(4):932-9
Jalal C, Uhlmann-Schiffler H, Stahl H.. Redundant role of
DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in
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Causevic M, Hislop RG, Kernohan NM, Carey FA, Kay RA,
Steele RJ, Fuller-Pace FV. Overexpression and polyubiquitylation of the DEAD-box RNA helicase p68 in colorectal
tumours. Oncogene. 2001 Nov 22;20(53):7734-43
Salzman DW, Shubert-Coleman J, Furneaux H.. P68 RNA
helicase unwinds the human let-7 microRNA precursor duplex
and is required for let-7-directed silencing of gene expression.
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Wei Y, Hu MH. [The study of P68 RNA helicase on cell
transformation]. Yi Chuan Xue Bao. 2001 Nov;28(11):991-6
Shin S, Rossow KL, Grande JP, Janknecht R.. Involvement of
RNA helicases p68 and p72 in colon cancer. Cancer Res.
2007 Aug 15;67(16):7572-8.
Hartmuth K, Urlaub H, Vornlocher HP, Will CL, Gentzel M,
Wilm M, Lührmann R. Protein composition of human
prespliceosomes isolated by a tobramycin affinity-selection
method. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):1671924
Yang L, Lin C, Sun SY, Zhao S, Liu ZR.. A double tyrosine
phosphorylation of P68 RNA helicase confers resistance to
TRAIL-induced
apoptosis.
Oncogene.
2007
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6;26(41):6082-92. Epub 2007 Mar 26.
Huang Y, Liu ZR. The ATPase, RNA unwinding, and RNA
binding activities of recombinant p68 RNA helicase. J Biol
Chem. 2002 Apr 12;277(15):12810-5
Wang H, Gao X, Huang Y, Yang J, Liu ZR.. P68 RNA helicase
is a nucleocytoplasmic shuttling protein. Cell Res. 2009
Dec;19(12):1388-400. Epub 2009 Sep 29.
Liu ZR. p68 RNA helicase is an essential human splicing factor
that acts at the U1 snRNA-5' splice site duplex. Mol Cell Biol.
2002 Aug;22(15):5443-50
Carter CL, Lin C, Liu CY, Yang L, Liu ZR.. Phosphorylated p68
RNA helicase activates Snail1 transcription by promoting
HDAC1 dissociation from the Snail1 promoter. Oncogene.
2010 Sep 30;29(39):5427-36. Epub 2010 Aug 2.
Guil S, Gattoni R, Carrascal M, Abián J, Stévenin J, Bach-Elias
M. Roles of hnRNP A1, SR proteins, and p68 helicase in c-H-
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5)
Liu ZR
Guo J, Hong F, Loke J, Yea S, Lim CL, Lee U, Mann DA,
Walsh MJ, Sninsky JJ, Friedman SL.. A DDX5 S480A
polymorphism is associated with increased transcription of
fibrogenic genes in hepatic stellate cells. J Biol Chem. 2010
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splicing by modulating a stem-loop structure at the 5' splice
site. Mol Cell Biol. 2011 May;31(9):1812-21. Epub 2011 Feb
22.
Kar A, Fushimi K, Zhou X, Ray P, Shi C, Chen X, Liu Z, Chen
S, Wu JY.. RNA helicase p68 (DDX5) regulates tau exon 10
Liu ZR. DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):44-47.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
This article should be referenced as such:
47
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(13;19)(q14;p13)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1319q14p13ID1512.html
DOI: 10.4267/2042/47270
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
cell commitment, and differentiation. Role in epithelial
mesenchymal transition (review in Slattery et al.,
2008).
Clinics and pathology
Disease
B cell acute lymphoblastic leukemia (B-ALL)
Note
An apparently identical t(13;19)(q14;p13) has been
described in 3 cases of chronic lymphocytic leukemia
(CLL) (Finn et al., 1998; Merup et al., 1998; Brown et
al., 1993).
References
Brown AG, Ross FM, Dunne EM, Steel CM, Weir-Thompson
EM. Evidence for a new tumour suppressor locus (DBM) in
human B-cell neoplasia telomeric to the retinoblastoma gene.
Nat Genet. 1993 Jan;3(1):67-72
Finn WG, Kay NE, Kroft SH, Church S, Peterson LC.
Secondary abnormalities of chromosome 6q in B-cell chronic
lymphocytic leukemia: a sequential study of karyotypic
instability in 51 patients. Am J Hematol. 1998 Nov;59(3):223-9
Epidemiology
Only one case to date of ALL with this translocation, a
19-year-old female patient with pre-B-ALL; she
achieved complete remission and (CR) was in
continuing CR 10 months later, at last follow up
(Barber et al., 2007).
Inukai T, Inaba T, Ikushima S, Look AT. The AD1 and AD2
transactivation domains of E2A are essential for the
antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Mol
Cell Biol. 1998 Oct;18(10):6035-43
Merup M, Jansson M, Corcoran M, Liu Y, Wu X, Rasool O,
Stellan B, Hermansson M, Juliusson G, Gahrton G, Einhorn S.
A FISH cosmid 'cocktail' for detection of 13q deletions in
chronic lymphocytic leukaemia--comparison with cytogenetics
and Southern hybridization. Leukemia. 1998 May;12(5):705-9
Genes involved and proteins
Note
The translocation involves TCF3 and an unknown
partner.
Barber KE, Harrison CJ, Broadfield ZJ, Stewart AR, Wright SL,
Martineau M, Strefford JC, Moorman AV. Molecular
cytogenetic
characterization
of
TCF3
(E2A)/19p13.3
rearrangements in B-cell precursor acute lymphoblastic
leukemia. Genes Chromosomes Cancer. 2007 May;46(5):47886
TCF3
Location
19p13.3
Protein
The E2A gene encodes two distinct basic helix-loophelix transcription factors, E12 (ITF1) and E47 (TCF3)
through alternative splicing. It forms homodimers and
heterodimers with other basic helix-loop-helix
transcription factors. Ubiquitously expressed during
development. Role in cell growth,
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Slattery C, Ryan MP, McMorrow T. E2A proteins: regulators of
cell phenotype in normal physiology and disease. Int J
Biochem Cell Biol. 2008;40(8):1431-6
This article should be referenced as such:
Huret JL. t(13;19)(q14;p13). Atlas Genet Cytogenet Oncol
Haematol. 2012; 16(1):48.
48
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(17;17)(q21;q24), del(17)(q21q24)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1717q21q24ID1497.html
DOI: 10.4267/2042/47271
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
RXR. At the DNA level, binds to retinoic acid response
elements (RARE). Ligand-dependent transcription
factor specifically involved in hematopoietic cells
differentiation and maturation.
Clinics and pathology
Disease
Acute myeloid leukaemia, M3 subtype (M3-AML)
PRKAR1A
Epidemiology
Location
17q24.2
Protein
Contains two tandem cAMP-binding domains. Forms
heterotetramers with PRKACA (protein kinase, cAMPdependent, catalytic, alpha), also called PKA. Interacts
with RARA, and regulates RARA transcriptional
activity.
Only one case to date, a 66-year-old male patient
(Catalano et al., 2007).
Cytology
Auer rods and fagot cells were absent.
Evolution
Complete remission was obtained with ATRA, and the
patient remains healthy 2 years after the diagnosis.
Result of the chromosomal
anomaly
Cytogenetics
Cytogenetics morphological
Hybrid gene
Cryptic deletion, FISH studies are needed to uncover
the rearrangement.
Description
5' PRKAR1A - 3' RARA. When we look closely to the
DNA sequences at the fusion breakpoints, they
correspond to the very end of exon 1 in PRKAR1A
(AGAGGTTGGAGAAG) and the very begining of
exon 2 in RARA (ATTGAGACCCAGAGCAGCAGT,
see sequences in Ensembl), although they were
described in exon 2 and exon 3 in the first and only
report of this rearrangement (Catalano et al., 2007).
Genes involved and proteins
RARA
Location
17q21.1
Protein
Contains Zn fingers and a ligand binding region.
Receptor for retinoic acid. Forms heterodimers with
Fusion protein
See figure 5' PRKAR1A - 3' RARA.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
49
t(17;17)(q21;q24), del(17)(q21q24)
Huret JL
differential regulation of alternately spliced messenger
ribonucleic acids. Endocrinology. 1997 Jan;138(1):169-81
Description
The fusion protein contains the dimerization domain
from PRKAR1A fused to the Zn fingers and ligand
binding regions from RARA.
Catalano A, Dawson MA, Somana K, Opat S, Schwarer A,
Campbell LJ, Iland H. The PRKAR1A gene is fused to RARA in
a new variant acute promyelocytic leukemia. Blood. 2007 Dec
1;110(12):4073-6
References
This article should be referenced as such:
Solberg R, Sandberg M, Natarajan V, Torjesen PA, Hansson
V, Jahnsen T, Taskén K. The human gene for the regulatory
subunit RI alpha of cyclic adenosine 3', 5'-monophosphatedependent protein kinase: two distinct promoters provide
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Huret JL. t(17;17)(q21;q24), del(17)(q21q24). Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(1):49-50.
50
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Deep Insight Section
MicroRNAs and Cancer
Federica Calore, Muller Fabbri
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University,
Columbus, OH 43210, USA (FC, MF)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Deep/MicroRNAandCancerID20101.html
DOI: 10.4267/2042/47272
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Keywords: microRNAs, non-coding RNAs, cancer, solid tumors, hematological malignancies, oncogene, tumor
suppressor gene, angiogenesis, metastasis, therapy, biomarkers.
Abstract
MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with gene expression regulatory functions, whose deregulation has been documented in almost all types of human cancer (both solid and hematological malignancies), with
respect to the non-tumoral tissue counterpart. After the initial discovery that the miRNome (defined as the full spectrum
of miRNAs expressed in a specific genome) is de-regulated in cancer, contributes to human carcinogenesis, and to the
mechanisms of angiogenesis and metastases (which are hallmarks of the malignant phenotype), new pieces of evidence
have been provided that miRNAs can be detected in several human body fluids, and can also be successfully used as
tumor biomarkers with diagnostic, prognostic and theranostic implications. These findings have cast a new
“translational” light on the research in the miRNA field, providing the rationale for a miRNA-based cancer therapy.
of different species. It has been demonstrated that each
miRNA can have hundreds of different targets and that
approximately 30% of the genes are regulated by at
least one miRNA (Bartel, 2004). MiRNAs are known
to be involved in several biological processes such as
cell cycle regulation, proliferation, apoptosis,
differentiation, development, metabolism, neuronal
patterning and aging (Bartel, 2004; Bagga et al., 2005;
Harfe, 2005; Boehm and Slack, 2006; Calin et al.,
2006; Arisawa et al., 2007; Carleton et al., 2007).
The biogenesis of miRNAs starts in the nucleus (Figure
1), where for the most part an RNA polymerase II
transcribes long primary precursors, up to several
kilobases (pri-miRNAs) (Ambros and Lee, 2004). Such
transcription occurs at the level of genomic regions
located within the introns or exons of protein-coding
genes (70%) or in intergenic areas (30%) (de Yebenes
and Ramiro, 2010).
Long, capped and polyadenylated pri-miRNAs (Cai et
al., 2004) are then processed by a ribonuclease III
(Drosha) and by the double-stranded DNA binding
protein DGCR8/Pasha, which enzymatically cut
Introduction
Tumor formation and progression is a complex
multistep process characterized by several consecutive
events: accumulation of genomic alterations,
uncontrolled proliferation, angiogenesis, invasion and
metastasis. Over the past few years an increasing
number of studies have highlighted the key role that
microRNAs have in the regulation of processes
described above.
MicroRNAs (miRNAs) are a family of single-stranded
non-coding RNAs (ncRNAs) between 19-24
nucleotides in length that regulate the expression of
target mRNAs both at transcriptional and translational
level. In plants such regulation occurs by perfect basepairing, usually in the 3' untranslated region (UTR) of
the targeted mRNA, whereas in mammals the basepairing is only partial (Lagos-Quintana et al., 2001; Lee
and Ambros, 2001; Hu et al., 2010).
Evolutionarily conserved among distantly related
organisms (Ambros, 2003), miRNA genes represent
approximately 1% of the predicted genes in the genome
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
51
MicroRNAs and Cancer
Calore F, Fabbri M
Figure 1. MiRNA biogenesis. MiRNA biogenesis begins inside the nucleus, then its processing and maturation take place in the
cytoplasm of an eukaryotic cell. MiRNAs are transcribed by RNA polymerase II as long primary transcript (pri-miRNAs) characterized by
hairpin structure and then cleaved by the enzyme Drosha in smaller molecules of nearly 70-nucleotides (pre-miRNAs). These precursors
are then exported to the cytoplasm by the Exportin 5/Ran-GTP complex and further processed by RNAse III Dicer, which generates
double-stranded-RNAs called duplex miRNA/miRNA* of 22-24 nucleotides. The strand corresponding to the mature miRNA is
incorporated into a large protein complex named RISC (RNA-induced silencing complex) and they interact with the 3’ UTR of the targeted
messenger RNA: if the complementarity between miRNA and the 3’UTR is perfect the latter is cleaved by RISC, whereas if the matching
is imperfect then translational repression occurs.
them into smaller fragments of 70-100 nucleotides
(pre-miRNAs) (Ambros, 2004). Precursor molecules
are then exported to the cytoplasm by Exportin 5 in a
Ran-GTP-dependent manner (Allawi et al., 2004;
Bohnsack et al., 2004) and through an additional step
mediated by the RNAse III Dicer 22 nucleotides
double-strand RNAs are generated (Bartel, 2004;
Esquela-Kerscher et al., 2005). The duplex miR/miR*
are finally incorporated into a large protein complex
named RISC (RNA-induced silencing complex): the
strand of the duplex which represents the mature
miRNA remains stably associated with RISC and
drives the complex to the target mRNA. If the basepairing between miRNA and the 3' UTR of the target
mRNA is perfect, the messenger is cleaved and
degraded (as it occurs in plants), if the complementarity
pairing is partial, translational silencing occurs without
mRNA degradation (mechanism described in animals)
(Achard et al., 2004; Gregory et al., 2006) (Figure 1).
The involvement of miRNAs in cancer arises from the
observation that these small molecules are differentially
expressed in neoplastic tissues in a tumor-specific
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
manner when compared to normal tissues (Volinia et
al., 2006), and in primary tumors when compared to
metastatic tissues (Tavazoie et al., 2008).
Moreover the genomic localization of miRNAs often
corresponds to tumor-associated regions, characterized
by
chromosomal
translocations,
genomic
amplifications, fragile sites, breakpoint regions in
proximity to oncogenes (OGs) or tumor suppressor
genes (TSGs) (Calin et al., 2004). In 2002 Calin et al.
showed that miR-15a and miR-16-1 genes are located
at a chromosomic region (13q14) deleted in more than
half of B cell chronic lymphocytic leukemias (B-CLL)
and that both genes are deleted or down-regulated in
the majority of CLL cases (68%) (Calin et al., 2002).
Based on the miRNA profiling analysis the following
studies aimed at investigating the functional role of
these molecules in tumorigenesis by using various
approaches, which have shed light on a more complex
role of miRNAs in cancer development: depending on
the context they can act as OGs or TSGs, and some of
them can even have a dual role of OG/TSG (Calin et
al., 2007) (Table 1).
52
MicroRNAs and Cancer
microRNA
Dysregulation in cancer
Calore F, Fabbri M
miRNA
target
Function
Reference(s)
miR-155
Upregulated in Burkitt's lymphoma,
Hodgkin disease, primary mediastinal
c-maf
non Hodgkin's lymphoma, CLL, AML,
lung, breast, pancreatic cancer
Oncogene
Metzler, Kluiver, Calin,
Garzon, Volinia, Greither
miR-21
Upregulated in glioblastoma, CLL, PTEN,
AML, prostate, pancreatic, gastric, PCDC4,
colon, breast, lung, liver cancer
TPM1
Oncogene
Meng, Frankel, Zhu, Ciafre,
Calin, Garzon, Volinia,
Meng
miR-17-92
cluster
Upregulated in breast, colon, lung,
pancreatic, prostate, gastric cancers, PTEN, Bim Oncogene
lymphomas
Volinia, Venturini
miR-372/373
Upregulated in testicular tumor
Oncogene
Voorhoeve
miR-221/222
Upregulated in thyroid, prostate,
P27Kip1
glioblastoma, colon, pancreas, stomach
Oncogene
Visone, Galardi, le Sage
miR-10b
Upregulated in breast cancer
HOXD10
Oncogene
Ma
Downregulated in CLL, prostate
BCL2,
CCND1,
WNT3A
Tumorsuppressor gene
Bullrich, Cimmino, Bonci
miR-15a
miR-16-1
and
LATS2
miR-29 family
Downregulated in lung cancer, CLL, TCL1,
AML,
breast
cancer
and MCL1,
cholangiocarcinoma
DNMT3s
Tumorsuppressor gene
Calin, Iorio, Garzon, Mott,
Fabbri, Pekarsky
Let-7 family
C-MYC,
Downregulated in lung and breast
HMGA2,
cancer
MYCN
Tumorsuppressor
gene/oncogene
Johnson Sampson, Lee,
Buechner, Brueckner, Iorio
miR-34 family
Downregulated in lung and pancreatic BCL2,
cancer
MYCN
Tumorsuppressor gene
Gallardo, Cole
Tumorsuppressor gene
Michael, Akao, Ibrahim
miR-143 and Downregulated in colorectal cancer
145 cluster
ERK5,
C-MYC
Table 1. The main de-regulated miRNAs in cancer.
Legend: CLL= chronic lymphocytic leukemia; AML= acute myeloid leukemia.
Moreover the use of miR-155 knock out mouse model
has revealed that miR-155 is strongly implicated into
the induction of Th2 lymphocyte differentiation and
altered cytokine production (de Yebenes and Ramiro,
2010).
Another miRNA which displays an oncogenic role is
miR-21. Chan et al. demonstrated that knockdown of
miR-21 in multiple glioblastoma cells induced caspase
activation and apoptosis, indicating that miR-21 could
function as an oncogene by blocking expression of
critical apoptosis-related genes (Abdellatif, 2010). In
fact miR-21 targets TSGs such as PTEN (phosphatase
and tensin homolog) (Choong et al., 2007), PDCD4
(programmed cell death 4) (Dillhoff et al., 2008) and
TPM1 (tropomyosin 1) (Beitzinger et al., 2007).
Similarly to miR-155 it is expressed in a wide range of
tumors such as glioblastoma (Ciafre et al., 2005), CLL
(Calin et al., 2005), AML (Calin
et al., 2008), prostate, pancreatic, gastric, colon, breast,
lung (Costinean et al., 2006) and liver cancer (Choong
et al., 2007).
miRNAs as oncogenes
Profiling studies have revealed that several miRNAs
show oncogenic properties. One of the first oncomiR
identified was miR-155 (Metzler et al., 2004; Kluiver et
al., 2005). It is located on chromosome 21 in a host
non-coding RNA called the B cell integration cluster
(BIC) and is highly expressed in pediatric Burkitt's
lymphoma (Metzler et al., 2004), Hodgkin disease
(Kluiver et al., 2005), primary mediastinal nonHodgkin's lymphoma (Calin et al., 2005) , chronic
lymphocytic leukemia (CLL) (Kluiver et al., 2005),
acute myelogenous leukemia (AML) (Calin et al.,
2008), lung, breast and pancreatic cancer (Volinia et
al., 2006; Greither et al., 2010). A study conducted by
Costinean et al. showed that transgenic mice with a Bcell targeted overexpression of miR-155 develop a
lymphoproliferative disease (polyclonal pre-leukemic
pre-B-cell proliferation followed by full-blown B-cell
malignancy) resembling the human diseases, indicating
that the deregulation mediated by miR-155 involves
both the initiation and progression of the disease
(Costinean et al., 2006).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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MicroRNAs and Cancer
Calore F, Fabbri M
MCL1 and TCL1 (Costinean et al., 2006; Mott et al.,
2007).
Among the tumor suppressor miRNAs there is the let-7
family. Johnson et al. demonstrated an inverse
correlation between the expression of the let-7 family
members and the expression of the oncogene RAS in
lung cancer tissue (Adai et al., 2005). Let-7 family
targets as well other onco-genes such as C-MYC
(Sampson et al., 2007), HMGA2 (high mobility group
A2) (Barakat et al., 2007) and MYCN (Buechner et al.,
2011). However, not all the members of this family
display a tumor suppressor role since in lung
adenocarcinoma let-7a-3 has an oncogenic function and
promotes tumor cell proliferation (Brueckner et al.,
2007).
The miR-34 family (comprising miR-34a, -34b and 34c) is downregulated in lung cancer tumor cells with
respect to normal tissue and their re-expression in
pancreatic cancer cell lines inhibits cell growth and
invasion, and induces apoptosis and cell cycle arrest in
G1 and G2/M (Gallardo et al., 2009). Similarly to the
tumor suppressor miRNAs described above, the miR34 family exerts its function by targeting anti apoptotic
mRNAs such as BLC2 and MYCN (Camps et al.,
2008).
The list of miRNAs having a tumor suppressor function
ends with the cluster miR-143 and -145. These
miRNAs, downregulated in several tumors (Akao et al.,
2007; Banaudha et al., 2011), have been found to target
ERK5 (extracellular signal-regulated kinase 5) and cMYC with consequent inhibition of tumor proliferation
and increased apoptosis (Akao et al., 2007; Ibrahim et
al., 2011).
The miR-17-92 cluster is characterized by six miRNAs
(miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and
miR-92-1) highly expressed in breast, colon, lung,
pancreatic, prostate and gastic cancer, lymphomas
(Costinean et al., 2006; Nagel et al., 2007). It has been
demonstrated that the miR-17-92 cluster induces B cell
proliferation.
Moreover,
transgenic
mice
overexpressing miR-17-92 in lymphocytes developed
lymphoproliferative disease and autoimmunity through
the inhibition of tumor suppressor Pten and the proapoptotic protein Bim (de Yebenes and Ramiro, 2010).
Other miRNAs that have an oncogenic role are miR372/373, which are involved in the development of
human testicular germ cell tumors by neutralizing the
TP53 pathway (Voorhoeve et al., 2006), miR-221/222
which induce proliferation of thyroid (Iorio et al.,
2007), prostate (Galardi et al., 2007) and glioblastoma
(Bai et al., 2007), miR-10b which promotes cell
migration and invasion in breast cancer (Derby et al.,
2007).
miRNAs as tumor suppressor
genes
If several miRNAs are known for their pro-oncogenic
role, then other miRNAs represent their counterpart by
acting as a TSG. Their silencing due to mutations,
chromosomal rearrangements or to promoter
methylation (Calin et al., 2002; Calin et al., 2005; Ishii
and Saito, 2006; Arisawa et al., 2007) contributes to the
initiation and progression of cancer.
MiR-15a and miR-16-1 represent a typical example of
TSG miRNA. Encoded as a cluster at the level of
chromosome 13q14.3, a region frequently deleted in
chronic lymphocytic leukemia (CLL) (Bullrich et al.,
2001), miR-15a and -16 display expression levels
inversely correlated to the BCL2 ones. These miRNAs
in fact induce apoptosis in leukemic cells by directly
targeting the anti-apoptotic gene (Calin et al., 2005).
Moreover, it has been demonstrated that miR-15a and 16 exert a tumor-suppressor role also in prostate cancer
by targeting BCL2, CCND1 (cyclin D1) and WNT3A
(encoding a protein which promotes cell survival,
proliferation and invasion) (Bonci et al., 2008). Taken
together, these findings harbor therapeutic implications
and bring new insights to the comprehension and
treatment of cancer.
Chromosome 7q32 hosts the miR-29 family
(comprising miR-29a, -29b and -29c), which is
downregulated in lung cancer, CLL, AML, breast
cancer and cholangiocarcinoma (Calin et al., 2005;
Mott et al., 2007; Calin et al., 2008). It has been
demonstrated that in lung cancer the expression of
miR-29 family members is inversely correlated with
DNMT3A and -3B (DNA methyltransferases 3A and
3B) and that these miRNAs directly target these
enzymes, inducing global hypomethyation of tumoral
cells (Calin et al., 2007) and reactivation of
methylation-silenced TSGs such as WWOX, FHIT,
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
miRNAs in solid tumors
Lung cancer
Lung cancer is the leading cause of cancer death
around the world (Jemal et al., 2009). Gao et al.
performed miRNA microarray expression profiling in
order to compare miRNAs expression in primary
squamous cell lung carcinoma with normal cells and
determine
miRNA
potential
relevance
to
clinicopathological factors and patient postoperative
survival times. They found out that miR-21 was
upregulated in nearly 75% of cancer specimens and that
this modulation was significantly correlated with
shortened survival time (Cheng et al., 2011).
Yanaihara and co-workers used the same approach and
correlated miRNA expression profiles with survival of
lung cancer, finding out that high miR-155 and low let7a-2 expression were correlated with poor survival.
Furthermore, they found a molecular signature for
subset of lung cancer: they identified six miRNAs
having a differential expression in adenocarcinoma and
squamous cell
cancer (mir-205, mir-99b, mir-203, mir-202, mir-102,
and mir-204-Prec). Among these, the expression of
miR-99b and miR-102 was found higher in
adenocarcinoma (Volinia et al., 2006).
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MicroRNAs and Cancer
Calore F, Fabbri M
IGF1R, SP1), inducing an upregulation of the tumor
suppressor gene BRCA1 (Heyn et al., 2011).
Colorectal cancer
In 2008 a study conducted by Schetter et al. the authors
performed miRNA microarray expression profiling
comparing 84 pairs of tumors (colon adenocarcinoma)
and adjacent non-tumoral tissues (Schetter et al., 2008).
They found 37 differentially expressed miRNAs;
among them miR-20a, -21, -106, -181b and -203 levels
were higher in tumor specimens. The overexpression of
miR-21 and its role in tumor proliferation in several
kind of cancers has already been described before. Also
miR-20a belongs to the miR-17-92 cluster, whose
overexpression promotes cell proliferation (Hayashita
et al., 2005) and increased tumor size.
One of the most recent tumor suppressor miRNAs
found in colorectal cancer is miR-137. Balaguer et al.
reported that this miRNA is constitutively expressed in
the normal colonic epithelium but during the early
events of colorectal carcinogenesis it is silenced
through promoter hyper-methylation. Moreover, its reexpression in vitro inhibits cell proliferation in a cell
specific manner. These findings suggest a prognostic
role for miR-137 (Balaguer et al., 2010).
It has been recently demonstrated by Sarver et al. that
miR-183 has an oncogenic role in colon cancer (but
also in synovial sarcoma and rhabdomyosarcoma)
through its regulation of the expression levels of 2
tumor suppressor genes, EGR1 and PTEN. The authors
also provided evidence that knockdown of miR-183
affects cellular migration and they suggest that
pharmaceutical intervention on tumor characterized by
the upregulation of miR-183 may be useful as anticancer therapy (Chen et al., 2010).
Hepatocellular carcinoma
One of the most common malignant tumors is
hepatocellular carcinoma. Murakami et al. analysed the
miRNA expression profiles in 25 specimens of
hepatocellular carcinoma compared with adjacent nontumoral tissues and nine chronic hepatitis specimens
(Murakami et al., 2006). miR-222, miR-17-92 and
miR-106a exhibited higher expression in tumor tissues
than in the normal ones and were found associated with
the tumor differentiation status.
Pineau et al. performed profiling studies on 104
hepatocellular carcinoma tissue specimens, 90
cirrhotic, 21 normal and 35 hepatocellular carcinoma
cell lines (Pineau et al., 2010). They found a 12
miRNA signature that characterizes tumor progression
starting from normal liver, to cirrhosis to full blown
tumor. Among them, miR-21, miR-221/222, miR-34a
and miR-224 were found overexpressed in the
progression signature. miR-224 overexpression is
connected with the regulation of cell proliferation, cell
migration and metastasis (Chemistry, 2010).
Su et al. reported that miR-101 is significantly
downregulated in hepatocellular carcinoma and that its
overexpression inhibits tumor development in nude
Yu et al. found a five-microRNA signature (let-7a,
miR-21, miR-137, miR-372, miR-182*) associated
with survival and cancer relapse in NSCLC (non-small
cell lung cancer) patients (Abdurakhmonov et al.,
2008). Another specific marker for squamous cell lung
carcinoma is miR-205, according to a microarray study
performed by Lebanony et al., who found a strong
association between the expression levels of miR-205
and squamous cell lung carcinoma histology (Barshack
et al., 2010).
In addition to the already mentioned miRNAs, miR-31
is found to act as an oncogenic miRNA by targeting
mRNAs encoding two anti-tumoral proteins, LATS2
(large tumor-suppressor 2) and PPP2R2A (PP2A
regulatory subunit B alpha isoform) (Anand et al.,
2010). Chou and co-workers discovered that miR-7
promotes EGFR-mediated tumorigenesis in lung cancer
by targeting ERF (Ets transcriptional repressor) thus
modulating cell growth (Choudhry and Catto, 2011).
However, miR-7 seems to have a dual function of
oncogene/tumor-suppressor miRNA. Xiong et al.
indeed found that overexpression of miR-7 in NSCLC
A549 cells inhibits cells proliferation and induces
apoptosis by targeting anti-tumoral protein Bcl-2 (Shao
et al., 2011).
Another miRNA that displays a tumor-suppressor role
in lung cancer is miR-451. Wang et al. demonstrated
not only that this miRNA is the most downregulated in
NSCLC tissues, but also that it regulates survival of
cells partially through the downregulation of the
oncogene RAB14 (Ras-related protein 14) (Bian et al.,
2011).
Breast cancer
Breast cancer is the second leading cause of cancer
deaths in the developed world and the most commonly
diagnosed cancer in women (Bonev et al., 2011). A
miRNA expression profile study for breast cancer was
conducted by Iorio et al. The authors found 13 miRNAs
differentially expressed between tumor and normal
tissues: among the upregulated ones there were
oncogenic miR-21 and miR-155, while miR-10b, let-7
miR-125b, miR-145 and miR-205 were found
downregulated (Calin et al., 2005). The latter directly
targets HER3 receptor and blocks the activation of
downstream Akt, inhibiting cell proliferation.
Moreover, miR-205 sensitizes cells to Gefitinib and
Lapatinib, two tyrosine-kinase inhibitors, promoting
apoptosis (Iorio et al., 2009).
Shi et al. found that miR-301 has an oncogenic role in
breast tumor by targeting FOXF2, BBC3, PTEN and
COL2A1. Its upregulation promotes proliferation,
migration, invasion and tumor formation. Moreover, by
cooperating with its host gene SKA2, miR-301
promotes the aggressive breast cancer phenotype with
nodal or distant relapses (Akao et al., 2011).
Heyn and co-workers identified miR-335 as a tumorsuppressor gene. It controls different factors of the
upstream BRCA1 regulatory pathway (such as ERa,
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MicroRNAs and Cancer
Calore F, Fabbri M
of the normal allele in leukemic cells of two CLL
patients, one of which with a family history of CLL and
breast cancer (Calin et al., 2005). A similar point
mutation, adjacent to the miR-16-1 locus has been
described in the CLL prone New Zealand Black mouse
strain model (Raveche et al., 2007). One of the most
frequent molecular hallmarks of the malignant, mostly
non-dividing B-cell of CLL, is the up-regulation of the
antiapoptotic BCL2. It has been demonstrated that both
miR-15a and miR-16 directly target BCL2 in CLL both
in vitro and in vivo (Calin et al., 2005; Ambs et al.,
2008), therefore suggesting that the miR-15a/16-1
cluster enacts a tumor suppressor function. Clinicians
are aware that CLL is characterized by recurrent and
common chromosomal aberrations, which harbor
prognostic implications. Some of the most frequent of
these abnormalities are the 13q deletion, the 17p
deletion and the 11q deletion. While CLL patients with
the 13q deletion experience the indolent form of the
disease (characterized by IGVH mutated and low levels
of the prognostic surrogate marker ZAP70), those with
the 17p or the 11q deletion (alone or in association with
the 13q), experience an aggressive form of the disease
(characterized by IGVH unmutated and high levels of
ZAP70) (Chiorazzi et al., 2005). Recently, a new
molecular network explaining the role of these
chromosomal aberrations and their prognostic
implications for human CLL has been described.
According to this model, the miR-15a/16-1 cluster
(located at 13q), directly targets the pro-apoptotic TP53
(located at 17p), which in turn transactivates the miR34b/34c cluster (located at 11q), directly targeting
ZAP70 (Fabbri et al., 2011). Also, TP53 is able to
transactivate the miR-15a/16-1 cluster, creating a feedforward regulatory loop (Fabbri et al., 2011). These
findings identify for the first time some of the
molecular effectors connecting these three recurrent
chromosomal aberrations in CLL and can explain both
their prognostic implications and the observed levels of
ZAP70 according to the degree of aggressiveness of the
disease. Recently, Klein et al. (Danilov et al., 2010)
generated two groups of transgenic mice models: one
mimicking the MDR and the other containing a specific
deletion of the miR-15a/16-1 cluster. Although the
same spectrum of clonal lymphoproliferative disorders
was observed in both animal models, the disease was
more aggressive in the MDR group than in the miR15a/16-1 group, suggesting that additional genetic
elements in the 13q14 region may affect the severity of
the
disease.
The
oncogene
TCL1
(T-cell
leukemia/lymphoma 1A) is over-expressed in the
aggressive CLL (Herling et al., 2006; Barlev et al.,
2010), and is regulated by miR-29b and miR-181b
(Costinean et al., 2006). Furthermore, miR-181a
directly targets BCL2 (Ebert et al., 2007), suggesting a
central role of miR-181 family and of the miR-15a/16-1
cluster in regulating BCL2 expression in CLL.
Stamatopoulos et al. (Stamatopoulos et al., 2009) found
that downregulation of miR-29c and miR-223 are
mice, sensitizes tumor cell lines to serum starvation and
chemotherapeutic treatment (Su et al., 2009).
Other tumor suppressor miRNAs are: miR-122,
normally downregulated in hepatocellular carcinoma,
whose overexpression induces apoptosis and cell cycle
arrest through targeting of BCLW (Chemistry, 2010);
miR-198, which inhibits migration and invasion in a cMET dependent manner (Akao et al., 2011); miR-125b,
which suppresses tumor cell growth in vitro and in vivo
and induces cell cycle arrest at G1/S acting as a tumor
suppressor gene through the suppression of LIN28B
(Bates et al., 2010), a promoter of cell proliferation and
metastasis through regulation of c-MYC and ECadherin (Ai et al., 2010).
miRNAs in hematological
malignancies
Similarly to what has been reported in solid tumors,
also in hematological malignancies the miRNome is
frequently de-regulated with respect to the normal cell
counterpart. Physiologic variations in miRNA
expression occur during normal hematopoiesis, and
affect differentiation and commitment of the
multipotent
hematologic
progenitor
(MPP).
Hematologic tumors represent abnormal blocks in
hematopoiesis. Interestingly, the aberrations of the
miRNome occurring in these tumors can be explained,
at least in some instances, as the result of the block of
differentiation leading to the development of the
malignancy. In other cases, the cause of the observed
de-regulation has not been clarified, but the role of the
de-regulated miRNAs in the acquisition of the
malignant phenotype has been understood, based on the
nature of the targeted genes.
miRNAs in leukemias
Chronic lymphocytic leukemia (CLL) is the most
frequent leukemia of the adult in the Western world.
Chromosomal aberrations recur in human CLL and
harbor diagnostic and prognostic implications.
Occurring in about 65% of cases, the 13q14 deletion is
the most frequent chromosomal aberration observed in
human CLL. Based on the analysis of a large number
of CLL cases with monoallelic 13q14 deletion, a
minimal deleted region (MDR) has been defined. This
MDR includes a long ncRNA, called DLEU2 (deleted
in leukemia 2), strongly conserved among vertebrates,
and the first exon of the DLEU1 gene, another ncRNA
(Migliazza et al., 2001; Chai et al., 2010). The miR15a/16-1 cluster is located within intron 4 of DLEU2,
and genetic alterations affecting DLEU2 mRNA
expression would also affect miR-15a/16-1 cluster
expression (Calin et al., 2002) . Therefore, the
expression of miR-15a/16-1 is reduced in the majority
of CLL patients carrying the 13q deletion (Calin et al.,
2002). Interestingly, the same miRNA cluster is
involved in cases of familial CLL, since a germ-line
mutation in the sequence of pre-miR-16-1 (which leads
to a reduced miR-16 expression both in vitro and in
vivo), has been identified associated with the deletion
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MicroRNAs and Cancer
Calore F, Fabbri M
leukemia (ALL) (Zanette et al., 2007; Nagel et al.,
2009). Recently, the miR-17–92 cluster has been
correlated with the development of mixed lineage
leukemia
(MLL)-rearranged
acute
leukemia
(Chemistry, 2010). Up-regulation of this cluster was
observed not only in MLL-associated AML, but also in
ALL, and is possibly due to both DNA copy number
amplification at 13q31 and to direct upregulation by
MLL fusions (Chemistry, 2010). Interestingly, a
specific miRNA signature of 4 miRNAs is able to
distinguish the two forms of acute leukemias (ALL
from AML (acute myeloid leukemia)) with an accuracy
rate of 98%. Indeed, higher expression of miR-128a
and miR-128b was found in ALL compared to AML,
whereas down-regulation of let-7b, miR-223 indicates
ALL vs AML (Science, 2007). At the moment, the
leukemogenic mechanism of miR-128b is still poorly
understood. Zhang et al., have identified a miRNA
signature in children with ALL complicated by central
nervous system (CNS) relapse (Ai et al., 2009). The
high-risk-of-relapse signature is composed of overexpression of miR-7, miR-198, and miR-663, and
down-regulation of miR-126, miR-345, miR-222, and
miR-551a. MiR-16 has a prognostic significance in
ALL. Indeed, Kaddar et al., found that low expression
of miR-16 is associated with a better ALL outcome
(Kaddar et al., 2009).
In AML with normal karyotype high levels of miR-10a,
-10b, members of let-7 and miR-29 families, and downregulation
of
miR-204,
identify
NPM1
(nucleophosmin-1) mutated versus unmutated cases
(Calin et al., 2008). Recently, Ovcharenko et al.,
confirmed that miR-10a expression is highly
characteristic for NPM1 mutated AML, and may
contribute to the intermediate risk of this condition by
interfering with the TP53 machinery, partly regulated
by its target MDM4 (murine double minute 4)
(Ovcharenko et al., 2011). Over-expression of miR-155
is associated with FLT3-ITD+ status, although there is
evidence that this up-regulation is actually independent
from FLT3 signaling (Calin et al., 2008). The fusion
oncoprotein AML1/ETO (generated by the t(8;21)
translocation), is the most frequent chromosomal
abnormality in AML, and causes epigenetic silencing
of miR-223, by recruiting chromatin remodeling
enzymes at an AML1-binding site on the pre-miR-223
gene (Fazi et al., 2007). By silencing miR-223
expression, the oncoprotein inhibits the differentiation
of myeloid precursors (promoted by high levels of
miR-223), therefore actively contributing to the
pathogenesis of this myeloproliferative disorder. A
central role in the pathogenesis of AML is also played
by miR-29b, a direct regulator of the expression of all
three DNA methyltransferases (Calin et al., 2007;
Garzon et al., 2009b). Re-expression of miR-29b
induces de-methylation and re-expression of
epigenetically silenced TSGs, such as ESR1 (estrogenreceptor alpha), and p15 (INK4b) (Garzon et al.,
2009b). Moreover, restoration of miR-29b in AML cell
predictive of treatment-free survival (TFS) and overall
survival (OS). Low expression of miR-223, miR-29b,
miR-29c, and miR-181 family are associated with
disease progression in CLL cases harboring the 17p
deletion, whereas patients carrying the trisomy 12
abnormality and high expression of miR-181a
experience a more aggressive variant of CLL (De
Martino et al., 2009). Interestingly, the miR-29 family
has been demonstrated to control key epigenetic
mechanisms (such as the expression of all three main
DNA methyltranferases) both in solid tumors and in
hematological malignancies (Calin et al., 2007; Garzon,
2009), therefore suggesting the involvement also of
miRNA-mediated
epigenetic
factors
in
the
pathogenesis and prognosis of human CLL.
Also miR-155 is up-regulated in CLL versus normal
CD19+ B lymphocytes, suggesting that this miRNA
might act as diagnostic biomarker of CLL (Marton et
al., 2008).
The Philadelphia chromosome (reciprocal translocation
t(9;22)) is the hallmark of the chronic myeloid
leukemia (CML), generating the chimeric protein BCRABL1, which is able to activate the miR-17-92 cluster,
together with the oncogene c-MYC, during the early
chronic phase, but not in blast crisis CML CD34+ cells
(Nagel et al., 2007). These findings suggest that the
miR-17-92 cluster contributes to early phase CML
pathogenesis, harboring CML diagnostic biomarker
properties. ABL1 is also a direct target of miR-203,
whose over-expression inhibits cancer cell proliferation
in an ABL1-dependent manner (Bueno et al., 2008).
Moreover, it has been shown that Philadelphia positive
CMLs, often present a reduced expression of miR-203
because of its promoter hyper-methylation, while no
methylation can be detected in other hematological
malignancies that do not carry ABL1 alterations
(Bueno et al., 2008). Finally, down-regulation of miR10a has been observed in about 70% of CMLs, with an
inverse correlation with the expression of the oncogene
USF2 (upstream stimulatory factor 2) (Agirre et al.,
2008). Overall, high levels of miR-17-92 cluster and
low expression of miR-203 and miR-10a seem to be
part of the diagnostic signature of human CML. More
recently, miR-451 has emerged as another key player in
CML. Indeed this miRNA can target BCR-ABL1,
which in turn can inhibit miR-451 expression, creating
a regulatory loop, whose disruption might have
therapeutic implications in the disease (Lopotova et al.,
2011). Another gene which inhibits cell growth and is
frequently down-regulated in CML is CCN3 (also
known as NOV or nephroblastoma overexpressed
gene). A possible mechanism of its down-regulation in
CML has been recently identified and is mediated by
miR-130a and miR-130b, which are up-regulated by
BCR-ABL1 in CML, and directly target CCN3,
contributing to leukemic cell proliferation (Suresh et
al., 2011).
Up-regulation of the miR-17-92 cluster has been
described also in B- and T-cell acute lymphocytic
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Indeed, miR-155 directly target SHIP (Src homology 2
domain-containing
inositol-5-phosphatase),
and
C/EBPbeta (CCAAT enhancer-binding protein beta),
two key regulators of the interleukin-6 signaling
pathway, therefore triggering a chain of events that
promotes the accumulation of large pre-B cells and
acute lymphoblastic leukemia/high-grade lymphoma
(Costinean et al., 2009). Also miR-155 knockout (KO)
mice models have been generated, showing that the
loss of miR-155 switches cytokine production toward
TH2 differentiation (de Yebenes and Ramiro, 2010),
and also compromises the ability of dendritic cells
(DC) to activate T cells, because of a defective antigen
presentation or abnormal co-stimulatory functions (de
Yebenes and Ramiro, 2010).
As observed in leukemias, also in NHLs, a specific
signature of 4 de-regulated miRNAs (namely miR-330,
-17-5p, -106a, and -210) can differentiate among
reactive lymph nodes, follicular lymphomas (FL), and
DLBCL (Hoefig et al., 2008). Noteworthy, miR-17-5p,
and miR-106a belong to two paralogous clusters
located on chromosome 13 and X, respectively, with a
well established oncogenic role both in solid and
hematological malignancies (Chang et al., 2008). The
miR-17-92 cluster is located in a region frequently
amplified in malignant B-cell lymphomas (Abbott et
al., 2005), and is overexpressed in over 60% of B-cell
lymphoma patients (Allawi et al., 2004). In murine
pluripotent cells from MYC-transgenic mice, overexpression of this miRNA cluster accelerates
lymphomagenesis (Allawi et al., 2004), whereas in
miR-17-92 TG mice models a higher than expected rate
of lymphoproliferative disorders and autoimmunity and
premature death was observed (de Yebenes and
Ramiro, 2010). These effects are at least in part due to
the direct targeting of the PTEN and BIM, which
controls B-lymphocyte apoptosis (de Yebenes and
Ramiro, 2010). The miR-106a-363 polycistron is also
overexpressed in 46% of acute and chronic human Tcell leukemias (Landais et al., 2007), claiming a role in
leukemogenesis. Interestingly, both miR-106b-25 and
miR-17-92 parologous clusters interfere with the
transforming growth factor-beta (TGF-beta) signaling
(Petrocca et al., 2008), which is inhibited in several
tumors (Derynck et al., 2001). Moreover, Ventura et al.
have shown that the miR-17-92 and miR-106b-25
double knockout mouse model has a more severe
phenotype than the miR-17-92 single knockout mouse
model (Ventura et al., 2008), suggesting that both
clusters are implicated in the control of apoptosis in
malignant lymphocytes. Interestingly, miR-17-5p and
miR-20a (which belong to the miR-17-92 cluster) are
induced by the proto-oncogene and transcription factor
c-MYC (Nakamoto et al., 2005), and in turn the cluster
directly targets E2F1, a c-MYC transactivated
transcription factor promoting cell-cycle progression
(Nakamoto et al., 2005). Therefore, the miR-17-92
cluster tightly regulates c-MYC-driven cell-cycle
progression. From a more translational perspective, it
lines and primary samples, suppresses the expression of
OGs such as MCL1, CXXC6, and CDK6, which are
direct targets of miR-29b (Garzon et al., 2009a).
Abnormal activation of the proto-oncogene c-KIT
contributes to leukemogenesis. Gao et al., found that
miR-193a is silenced by promoter hyper-methylation in
AML, and since this miRNA directly targets c-KIT,
this epigenetic silencing is responsible, at least in part,
for the aberrant up-regulation of the oncogene in AML
(Cheng et al., 2011). Indeed, restoration of miR-193a
expression by de-methylating agents, reduces the
expression of c-KIT and induces cancer cell apoptosis
and granulocytic differentiation (Cheng et al., 2011).
Similarly, also miR-193b directly targets c-KIT in
AML (Cheng et al., 2011). By using a novel approach
based on the integration of miRNA and mRNA
expression profiles, Havelange et al., found a strong
positive correlation between miR-10 and miR-20a and
HOX-related genes, a significant inverse correlation
between genes involved in immunity and inflammation
(such as IRF7 and TLR4) and a panel of 4 miRNAs
(namely, miR-181a, -181b, -155, and -146), and a
strong direct correlation between miR-23, -26a, -128a,
and -145 and pro-apoptotic genes (such as BIM and
PTEN) (Havelange et al., 2011). Also miR-100 has
been described as an OG in AML, by targeting the TSG
RBSP3 (CTD (carboxy-terminal domain, RNA
polymerase II, polypeptide A) small phosphatase-like)
(Cao et al., 2011). Also in AML, miR-17/20/93/106
have been shown to promote hematopoietic cell
expansion by targeting sequestosome 1-regulated
pathways in mice (Meenhuis et al., 2011). Downregulation of miR-29a and miR-142-3p has been
observed in AML with respect to controls (Bian et al.,
2011), and miR-29a contributes to counteract leukemic
proliferation by directly targeting the proto-oncogene
SKI (Teichler et al., 2011).
miRNAs in lymphomas
De-regulation of miRNAs has been reported also in non
Hodgkin lymphomas (NHL) and in Hodgkin's disease
(HL). The first evidence of an involvement of miRNAs
in lymphomagenesis was provided by Eis et al. who
observed that the final part of the B-cell integration
cluster (BIC) non-coding RNA (ncRNA), where miR155 is located (Chen and Meister, 2005), was able to
accelerate MYC-mediated lymphomagenesis in a
chicken model (Bashirullah et al., 2003). Subsequently,
high levels of BIC/miR-155 were described also in
pediatric Burkitt's lymphoma (BL) (Metzler et al.,
2004), in diffuse large B-cell lymphoma (DLBCL)
(Lawrie, 2007; Hoefiget al., 2008), and in HL (Kluiver
et al., 2005; Abdurakhmonov et al., 2008; Van
Vlierberghe et al., 2009). In a B-cell specific miR-155
transgenic (TG) mouse model the onset of an acute
lymphoblastic leukemia/high-grade lymphoma at
approximately 9 months of age was observed
(Costinean et al., 2006). In these TG mice, the B-cell
precursors with the highest miR-155 expression were at
the origin of the leukemias (Costinean et al., 2009).
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has been also demonstrated that over-expression of the
miR-17-92 cluster also significantly increases the
resistance to radiotherapy in human mantle cell
lymphoma cells (Ahn et al., 2010), revealing a role for
this cluster as a theranostic biomarker. MiR-34a is
negatively regulated by c-MYC (Abdurakhmonov et
al., 2008). In c-MYC over-expressing B-lymphocytes
miR-34a confers drug resistance by inhibiting TP53dependent bortezomib-induced apoptosis (Sotillo et al.,
2011). Finally, down-regulation of miR-143 and miR145 has been described in B-cell lymphomas and
leukemias (Akao et al., 2007), and re-expression of
these miRNAs in a Burkitt lymphoma cell line
demonstrated a dose-dependent growth inhibitory
effect, mediated in part by miRNA-induced
downregulation of the oncogene ERK5 (Akao et al.,
2007).
In HL, Navarro et al. identified a distinctive signature
of 25 miRNAs able to distinguish HL from reactive
lymph nodes, and 36 miRNAs differentially expressed
in the nodular sclerosis and mixed cellularity subtypes
of HL (Navarro et al., 2007). Interestingly, 3 miRNAs
(namely, miR-96, -128a, and -128b) are selectively
downregulated in HL cells with Epstein–Barr virus
(EBV) infection, but only one of these miRNAs is part
of the signature of 25 de-regulated miRNAs in HL
versus reactive lymph nodes, suggesting that EBV
might not be relevant for HL pathogenesis (Navarro et
al., 2007). Down-regulation of miR-150 and overexpression of miR-155 frequently occur in HL cell
lines (Gibcus et al., 2009). Since HL develops in the
lymph node germinal center, and high levels of miR155 have been described in the germinal center also
during normal lymphopoiesis, it can be postulated that
the observed over-expression of miR-155 in HL might
result from an abnormal block of lymphocyte
differentiation at the germinal center level. Van
Vlierberghe et al., have compared miRNA profiles of
microdissected Reed-Sternberg cells and Hodgkin cell
lines versus CD77+ B-cells (Van Vlierberghe et al.,
2009). In this study a profile of 12 over and 3 underexpressed miRNAs was identified (Van Vlierberghe et
al., 2009), showing only a partial overlap with
Navarro's profile. This discrepancy might be due to the
different procedure used to collect HL cells. Finally,
also in HL miRNA expression profile can predict
prognosis. Indeed, low levels of miR-135a are
associated with a higher relapse risk and a shorter
disease-free survival (Gallardo et al., 2009). A possible
molecular explanation for this effect is that miR-135a
directly targets the kinase JAK2 (Janus Kinase 2).
Therefore, low levels of miR-135a are associated with
higher expression of JAK2, which leads to upregulation of the antiapoptotic BCL-XL, therefore
leading to reduced apoptosis and increased cell
proliferation (Gallardo et al., 2009).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
miRNAs in body fluids as tumor
biomarkers
MiRNAs have been successfully detected in blood and
other human fluids. It has been shown that they
circulate wrapped in circulating microvescicles called
"exosomes" (Bar et al., 2008), and therefore are
extremely stable and resistant to degradation (Aumiller
and Forstemann, 2008; Kroh et al., 2010). In 2010,
Weber et al. determined miRNA expression in 12
different types of body fluids (amniotic fluid, breast
milk, bronchial lavage, cerebrospinal fluid (CSF),
colostrum, peritoneal fluid, plasma, pleural fluid,
saliva, seminal fluid, tears and urine) collected from
healthy individuals, and showed that the highest
concentrations of miRNAs were found in tears and the
lowest in CSF, pleural fluid and urine (Black et al.,
2010). The ability to detect miRNAs in body fluids has
generated interest in their possible role as tumoral
biomarkers. Several studies have demonstrated that
miRNAs can indeed be successfully employed both as
cancer diagnostic and prognostic biomarkers both in
solid and in hematological malignancies. Table 2
summarizes some of these studies.
miRNAs in body fluids as tumor
biomarkers in solid tumors
Diagnostic biomarkers
The first evidence that circulating miRNAs can be
effectively used to diagnose cancer was provided by
Mitchell et al. in 2008 (Bar et al., 2008). They found
that higher levels of miR-141 in the serum of 25
patients affected by prostate cancer, compared with 25
healthy control donors identify patients affected by
cancer with a sensitivity of 60%, and a specificity of
100% (Bar et al., 2008). Subsequently, Taylor et al.
showed that a signature of 8 circulating miRNAs
(enclosed in tumor-derived exosomes of endocytic
origin) can be used as diagnostic biomarker of ovarian
cancer (Chang et al., 2008). Moreover, in a comparison
of 152 patients affected by NSCLC versus 75 healthy
donors, Chen et al., identified higher levels of miR-25,
and miR-223 in the serum of cancer patients (Aumiller
and Forstemann, 2008). Interestingly, these Authors
also demonstrated that circulating miRNAs resist
treatments with HCl, NaOH, and repeated freeze and
thaw cycles, therefore acting as stable, reliable
biomarkers (Aumiller and Forstemann, 2008). Patients
affected by pancreatic cancer have higher
concentrations of circulating miR-210 (Bar et al., 2008)
, -200a, and -200b (Chemistry, 2010), suggesting that
these miRNAs might be used to successfully screen for
pancreatic cancer. High levels of circulating miR-29a, 92 and -17-3p have been found in patients affected by
colorectal cancer (Anand et al., 2010).
59
MicroRNAs and Cancer
Cancer
Expression
cancer
Calore F, Fabbri M
in
Biomarker property
Body fluid
miRNA
Reference
Solid Tumors
Pancreas
High
D, D, D
Blood
200a, 200b, 210
Ho, Weber
Prostate
High
(D,P), P
Blood
141, 375
Mitchell, Brase
Colorectal
High
(D,P),D, D
Blood
29a, 92, 17-3p
Ng, Huang
OSCC
High
D
Blood
31
Liu
Breast
High
(D,P),D,(D,P)
Blood
21, 195, let-7a
Asaga, Heneghan
Lung
High
D,D
Blood
25, 223
Lu
HCC
Lower ratio
D
Blood
92a/638
Shigoka
Lung, Gastric High
D,D,D
Pleural effusion 24, 26a, 30d
Xie
Bladder
High
D,D,D
Urine
126, 182, 199a
Hanke
OSCC
High
D
Saliva
31
Liu
OSCC
Low
D
Saliva
200a, 125a
Park
Bladder
Higher ratio
D
Urine
126/152 and 182/152
Hanke
(D,P), (D,P), D
Blood
21, 155, 210
Lawrie
Hematological malignancies
DLBCL
High
Table 2. MiRNAs detectable in body fluids and their diagnostic and prognostic significance for cancer patients.
Legend: The column "Biomarker property" should be read as each letter (or in parenthesis letters) referred to the miRNA reported in the
column "miRNA", according to the sequence order in which these miRNAs are reported. D= Diagnostic biomarker; P= Prognostic
biomarker; (D,P)= Diagnostic and Prognostic biomarker. OSCC= Oral Squamous Cell Carcinoma; HCC= Hepatocellular Carcinoma;
DLBCL= Diffuse Large B-Cell Lymphoma.
Interestingly, miR-92 is not elevated in the plasma of
patients with irritable bowel disease, suggesting a role
for this miRNA in the differential diagnosis between
this benign condition and cancer. Moreover, the
increased levels of circulating miR-29a and -92 occur
already in presence of pre-cancerous conditions such as
colon adenomas (Anand et al., 2010), revealing that the
de-regulation of these two miRNAs is an early event in
colon carcinogenesis and their increased plasma
concentration might be helpful for the very early (even
pre-cancerous) phase of colorectal tumorigenesis. In
breast cancer, Asaga et al. showed that serum
concentrations of miR-21 correlates with the presence
and extent of breast cancer (Asaga et al., 2011),
whereas Heneghan et al., showed that circulating miR195 differentiates breast cancer from other
malignancies and is a potential biomarker for the
detection of non-invasive and early stage disease
(Henegan et al., 2010). Finally, in oral squamous cell
carcinoma (OSCC) high levels of circulating miR-31
differentiate patients from healthy controls and the
concentration of this miRNA decreases after surgical
resection of the tumor (Anand et al., 2010), suggesting
that miR-31 might be helpful also for the early
detection of OSCC recurrence.
In addition to blood and plasma, miRNAs can be
detected also in other body fluids and have diagnostic
biomarker properties. High levels of miR-31 (Anand et
al., 2010), and lower levels of miR-200a and -125a
(Addo-Quaye et al., 2009) have been identified in the
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
saliva of OSCC patients. An increased expression of
miR-126, -182, and -199a has been described in the
urine of patients affected by bladder cancer with
respect to healthy controls (Hanke et al., 2010),
whereas the ratio miR-126/miR-152 and miR-182/miR152 is higher in patients affected by bladder cancer
versus carriers of urinary tract infections, with a
sensitivity of 72% and 55%, respectively, and a
specificity of 82% (Hanke et al., 2010). Similarly, in
the blood of patients with hepatocellular carcinoma
(HCC), Shigoka et al. found that the ratio of miR92a/miR-638 is lower than healthy controls, suggesting
a possible role of this non-coding RNA parameter in
the diagnosis of HCC. Also in malignant pleural
effusions of patients affected by lung cancer and gastric
carcinoma, higher levels of miR-24, -26a, and -30d
compared to controls were reported (Dai et al., 2010).
Prognostic biomarkers
In addition to their role as diagnostic biomarkers,
miRNA can also act as prognostic and theranostic in
several human solid tumors.
Low levels of circulating let-7a are associated with
node positive breast cancer, compared to negative node
disease (Henegan et al., 2010), whereas higher levels of
miR-21 can be detected in patients with advanced
breast cancer with respect to early stage disease (Asaga
et al., 2011). Similarly, circulating miR-29a expression
differs in early stage versus advanced colorectal cancer
(Anand et al., 2010). In prostate cancer, higher serum
levels of miR-375 and -141 are found in patients with
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MicroRNAs and Cancer
Calore F, Fabbri M
advanced disease (Brase et al., 2011), whereas higher
circulating miR-21 was found in hormone refractory
prostate cancer, with respect to benign prostatic
hyperplasia, localized prostate cancer and hormone
dependent prostate cancer (Bo et al., 2011).
the systemic circulation distant sites in which they can
finally proliferate as secondary tumors.
Depending on their role in the modulation of these
processes, miRNAs can be subdivided into two groups:
the anti-angiogenic and the pro-angiogenic ones.
Poliseno et al. demonstrated that the miR-221/miR-222
family has anti-angiogenic properties as it inhibits the
angiogenic activity of stem cell factor SCF by targeting
its receptor c-KIT in endothelial cells (Poliseno et al.,
2006).
Since miR-21 plays a crucial role in cancer progression
Sabatel et al. pondered whether it could also be
involved in angiogenesis (Sabatel et al., 2011). Their in
vitro and in vivo study revealed that mir-21 is a
negative regulator of endothelial cell migration and
tubulogenesis. Angiogenesis inhibition would occur
through the targeting of RhoB, a small GTPase which
is responsible for the assembly of actin stress fibers
(Aspenstrom et al., 2004). However, it seems that miR21 has a dual role in the regulation of angiogenesis. Liu
et al. in fact found that the overexpression of miR-21 in
prostate cancer cell line increases the expression of
HIF-1a and VEGF through the AKT and ERK
pathway, thus acting as a pro-angiogenetic miRNA
(Ayala de la Pena et al., 2011). Other miRNAs are
known to be positive regulators for angiogenesis. For
example, in vascular endothelial cells miR-130a
downregulates the expression of the antiangiogenic
homeobox genes HOXA5 and GAX in response to
mitogens, proangiogenic and proinflammatory factors
(Aumiller and Forstemann, 2008).
By using in vitro and in vivo studies Fang et al. found
that miR-93 promotes angiogenesis and tumor growth
by suppressing integrin-b8 expression and enhancing
endothelial activity (Fang et al., 2011). Indeed this
miRNA induces blood vessels formation, cell
proliferation and migration by targeting the cell deathinducing antigen integrin-b8. The authors cannot
exclude that miR-93 may also target other genes
involved in tumorigenesis and angiogenesis.
Also, the miR-17-92 cluster promotes angiogenesis by
inhibiting the expression of antiangiogenic protein
thrompospondin-1 (TSP1) and connective tissue
growth factor (CTGF) (Dews et al., 2006); miR-378
overexpression in glioblastoma cell line U87 enhanced
angiogenesis and tumor growth through its targeting of
tumor suppressor proteins SUFU and FUS-1 (Barakat
et al., 2007); miR-296 is highly expressed in primary
human brain microvascular endothelial cells and
contributes to angiogenesis by directly targeting the
hepatocyte growth factor-regulated tyrosine kinase
substrate (HGS) mRNA, leading to decreased levels of
HGS and thereby reducing HGS-mediated degradation
of the growth factor receptors VEGFR2 and PDGFR-b
(Gabriely et al., 2008).
Also in the regulation of the metastatic process
miRNAs can be divided into two categories: prometastatic (such as miR-340, miR-92a, miR-10b, miR-
miRNAs in body fluids as tumor
biomarkers in hematological
malignancies
Diagnostic biomarkers
Higher levels of circulating miR-21, -155 and -210
have been described in patients affected by diffuse
large B-cell lymphoma (DLBCL), compared to controls
(Lawrie, 2008). Interestingly, the same group had
previously shown that the expression of miR-155 in
primary DLBCLs distinguishes between the activated
B-cell phenotype (ABC) (higher expression of miR155), than in the germinal center B-cell-like phenotype
(GCB) (lower expression of miR-155) (Chen and
Meister, 2005; Lawrie, 2007). Since, the 5-year
survival rates of the ABC and the GCB subtypes of
DLBCL are 30% and 59%, respectively (Kovanen et
al., 2003), miR-155 expression in DLBCL has a
prognostic value. A correlation between miR-155 and
NFkB expression was found in DLBCL cell lines and
patients (Abu-Elneel et al., 2008). In addition to miR155, high levels of miR-21 and miR-221 are also
associated with ABC-DLBCL and severe prognosis (de
Yebenes and Ramiro, 2010). It would be interesting to
investigate whether the expression of circulating miR155 correlates with the expression of this miRNA in
primary DLBCL, since it would indicate that miR-155
is a diagnostic biomarkers not only to put the diagnosis
of DLBCL, but also of subtype of DLBCL.
Prognostic biomarkers
In DLBCL, increased serum levels of miR-21 are
associated with a longer relapse-free survival (Lawrie,
2008), indicating that circulating miR-21 harbors
prognostic implications in patients affected by DLBCL.
Overall, miRNAs can be detected in body fluids and
increasing evidence shows that their expression in these
fluids allows the diagnosis of cancer histotype and, in
some cases histologic subtype. Finally, specific
signatures of de-regulated miRNAs in body fluids
harbor prognostic implications. These discoveries cast
a new light on the translational implications of research
in the miRNA field, by suggesting that these noncoding RNAs could be detected non-invasively and
provide key diagnostic and prognostic clinical
information.
miRNAs in invasion, angiogenesis
and metastasis
In the last few years several studies have pointed out a
critical role of miRNAs in tumor angiogenesis and
metastasis. By regulating these processes miRNAs
have emerged as crucial players, thus allowing primary
tumor cells to invade adjacent tissues and reach through
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hepatocellular carcinoma miR-34a is also downregulated (Li et al., 2009) and its expression is
inversely correlated with that of the receptor for the
hepatocyte growth factor c-MET (Leelawat et al.,
2006), involved in cell invasion and metastasis. In their
study the Authors demonstrated that miR-34a targets cMET when ectopically expressed in Hep-G2 cells and
observed reduced cell scattering, migration and
invasion.
Crk (v-crk sarcoma virus CT 10 oncogene homolog) is
a protein that regulates cell motility, differentiation and
adhesion (Kobashigawa et al., 2007). High expression
levels of this protein are found in several human tumors
such as breast, ovarian, lung, brain, stomach and
chondrosarcoma (Wang et al., 2007) and knock down
of Crk decreases cell migration and invasion
(Rodrigues et al., 2005; Wang et al., 2007). Crawford et
al. showed that Crk is a functional target of miR-126 in
NSCLC tumors and that overexpression of miR-126
induces a decrease in adhesion, migration and invasion
(Crawford et al., 2008).
Finally, the list of anti-metastatic miRNAs includes
miR-206 and miR-335. In a manuscript published in
2008 Tavazoie and coworkers took under consideration
a set of miRNAs whose expression was lost in human
breast cancer cells (Tavazoie et al., 2008). Among
these they considered miR-206 and miR-335. By
restoring their expression through retroviral
transduction they found that the ability of these cells to
migrate to the lung was lost. MiR-335 exerts its antimetastatic role by targeting PTPRN2 (receptor-type
tyrosine protein phosphatase) (Varadi et al., 2005),
MERTK (the c-Mer tyrosine kinase) (Graham et al.,
1995), SOX4 (SRY-box containing transcription
factor), the progenitor cell transcription factor (van de
Wetering et al., 1993; Hoser et al., 2007) and TNC
(tenascin C) (Ilunga et al., 2004), which is an
extracellular component of the matrix.
373/520c) or anti-metastatic (such as miR-101, miR34a, miR-126, miR-148a, miR-335) ones.
In breast cancer reduced miR-340 expression is
associate with tumor cell migration, invasion and poor
prognosis (Dong et al., 2011).
Of the six mature miRNAs produced by the miR-1792a cluster, miR-92a is involved in the metastatization
process. It has been reported that miR-92a is highly
expressed in tumor tissue from ESCC (Esophageal
Squamous Cell Carcinoma) patients (Cai et al., 2008).
Chen et al. verified whether there is a correlation
between the relative expression of miR-92a in tumor
and normal tissues and lymph node metastasis in ESCC
patients. Not only they found that miR-92a promotes
ESCC cell migration and invasion through the
inhibition (by direct targeting) of CDH1, which is
known to mediate cell-to-cell adhesion, but also that
ESCC patients with up-regulated miR-92a are prone to
lymph node metastasis and poor prognosis (Bao et al.,
2011).
In 2007, Ma et al. reported that miR-10b is highly
expressed in metastatic breast cancer cells, when
compared with non-metastatic cells. However, when
overexpressed in the latter it promotes robust invasion
and metastasis. Induced by the transcription factor
Twist, miR-10 inhibits the translation of the messenger
RNA encoding HOXD10 (homeobox D10), thus
increasing the expression of the pro-metastatic gene
RHOC and leading to tumor invasion and metastasis
(Derby et al., 2007).
Through the transduction of a non-metastatic breast
cancer cell line with a miRNA expression library
Huang et al. studied which miRNAs could allow the
cells to migrate. MiR-373 and miR-520c were found to
promote cell invasion and metastasis both in vitro and
in vivo through the inhibition of the expression of
CD44, a protein involved in cell adhesion
(Abdurakhmonov et al., 2008).
As previously reported, miRNAs are known also to
have an anti-metastatic role. One of them is miR-101,
whose expression decreases during prostate cancer
progression, as depicted by Varambally et al.
(Varambally et al., 2008). The authors showed that
during this process there's a negative correlation
between the expression of miR-101 and EZH2, a
mammalian histone methyltransferase overexpressed in
solid tumors (Varambally et al., 2002) and involved in
the epigenetic silencing (Yu et al., 2007; Cao et al.,
2008) of genes responsible for tumor invasion and
metastasis.
By performing experiments based on computational
analysis the authors showed also that miR-101 targets
EZH2. Loss of miR-101, paralleled by increased levels
of EZH2 in the tumor, leads to dysregulation of
epigenetic pathways and cancer progression.
Another miRNA typically downregulated in tumors
(colorectal cancer (Tazawa et al., 2007), pancreatic
cancer (Chang et al., 2007), and neuroblastoma (Welch
et al., 2007)) is miR-34a. Li et al. observed that in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Therapeutic implications of miRNAs
in oncology
The involvement of miRNAs in different aspects of
human carcinogenesis, such as cell proliferation,
apoptosis, differentiation, angiogenesis, motility and
metastasis, has raised the question whether reverting
these aberrations of the miRNome can be effectively
used for therapeutic purposes. Preclinical data
encourage this hypothesis and provide the biological
rationale for clinical studies in this direction. Reexpression of miRNAs down-regulated in cancer (e.g.
miR-15a and miR-16 in BCL2 positive CLL) and/or
silencing of miRNAs up-regulated in the tumor (e.g.
miR-155 in lung cancer) may lead to cancer cell
apoptosis and exert a therapeutic effect. Before this
becomes a reality in patients though, several issues
need to be solved. First, there is a need to know the full
spectrum of targets and effects that a given miRNA has
on a given genome. It has been estimated that a single
miRNA cluster (namely, the miR-15a/16-1 cluster) is
62
MicroRNAs and Cancer
Calore F, Fabbri M
able to affect, directly and indirectly, the expression of
about 14% of the whole human genome (Calin et al.,
2008). Also it is clear that each miRNA is able to target
both OGs and TSGs, and that the phenotype induced by
the external manipulation of a miRNA is the result of
this combined targeting effect on several genes.
Therefore, one of the goals of the preclinical research is
to fully clarify this aspect before any clinical
application can even be taken into consideration.
Secondly, it needs to be established how can we reach a
tumor-specific delivery of the miRNAs of interest?
This question is more general, and involves the whole
field of gene therapy, being not limited to the research
on miRNAs. The advent of nanoparticles, able to target
tumor-specific antigens hopefully will address this
concern and allow tumor specificity. Another aspect of
relevance consists in determining how the modulation
of miRNA expression can integrate the existing anticancer therapies (chemo-, radio-, hormonotherapy)?
Interestingly, some studies have been published
showing that miRNAs can restore sensitivity to current
therapeutic options to which the tumors became
resistant, and this encourages a certain optimist on
miRNA-inclusive association regimens. The other
questions on what is the best formulation of miRNAs to
be administered, and what are the pharmacokinetics
and pharmacodynamics of these ncRNAs in humans
will be answered (as always) by the established phases
of the clinical studies.
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The involvement of miRNAs in human cancer
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as molecular biomarkers (the published studies still
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This article should be referenced as such:
Calore F, Fabbri M. MicroRNAs and Cancer. Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(1):51-69.
Shao GC, Luo LF, Jiang SW, Deng CY, Xiong YZ, Li FE. A C/T
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Case Report Section
Paper co-edited with the European LeukemiaNet
Unbalanced rearrangement der(9;18)(p10;q10) and
JAK2 V617F mutation in a patient with AML
following post-polycythemic myelofibrosis
Francesca Cambosu, Giuseppina Fogu, Paola Maria Campus, Claudio Fozza, Luigi Podda,
Andrea Montella, Maurizio Longinotti
Clinical Genetics, Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B 07100
Sassari, Italy (FC, GF, AM); Azienda Ospedaliero-Universitaria Sassari, Italy (PMC, CF, LP, AM, ML);
Institute of Hematology, University of Sassari, Italy (CF, LP, ML)
Published in Atlas Database: September 2011
Online updated version : http://AtlasGeneticsOncology.org/Reports/der918p10q10CambosuID100057.html
DOI: 10.4267/2042/47273
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Diagnosis
Polycythemia vera. Myelofibrosis: hypocellular bone
marrow with marked increase in reticulin fibres. AML
M2.
Clinics
Age and sex
66 years old male patient.
Previous history
No preleukemia. No previous malignancy. No inborn
condition of note.
Organomegaly
Hepatomegaly (enlarged liver (+ 20 cm)),
splenomegaly, no enlarged lymph nodes , no central
nervous system involvement.
Survival
Date of diagnosis: 01-1980
Treatment
Bleeding therapy and acethylsalicylic acid. 2005 -2008:
Etanercept (anti-TNF alpha). 2007: Hydroxyurea. Sept.
2008: Splenectomy. Feb. 2008: Pomalidomide,
suspended after 1 month because of a severe
neutropeny. Feb 2009: Bone Marrow allograft.
Complete remission : no (March-November 2009:
complete hematological remission; molecular remission
not reached (JAK-2 positivity in June 2009))
Treatment related death : no
Relapse : no
Status: Death. Last follow up: 11-2010 (due to
gastrointestinal hemorrhage).
Survival: nearly 30 years.
Blood
WBC : 46 X 109/l
HB : 8.5 g/dl
Platelets : 239 X 109/l
Blasts : 15%
Bone marrow : 25%
Cyto-Pathology
Classification
Karyotype
Cytology: NA
Immunophenotype: NA
Rearranged Ig Tcr: NA
Pathology: NA
Electron microscopy: NA
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Sample: Bone marrow biopsy in Dec. 2008
Culture time: 24 and 48 h.
Banding: Cytogenetic analysis performed in QFQ
banding; band level: 400.
Results
46,XY, +9,der(9;18)(p10;q10) in 25/25 cells scored.
70
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Cambosu F, et al.
Comments
Probes: whole-chromosome painting probes (wcp) and
centromeric (CEP) probes of chromosomes 9 (9p11-q11 alpha
satellite DNA) and 18 (D18Z1) (Abbott Molecular/Vysis).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
71
Polycythemia Vera (PV) is a clonal myeloproliferative
disorder characterized by excessive erythrocyte
production, which may evolve into myelofibrosis and
acute
myeloid
leukemia.
Transformation
to
myelofibrosis occurs in 15-20% of cases and leukemic
transformation in 5-10% of patients. The median
survival time is 8-11 years and the median age at
diagnosis is over 60 years. Normal karyotype is present
at diagnosis in the majority of patients, while during
transformation several acquired chromosome anomalies
are present as trisomy 9 and gains in 9p.
The activating JAK2 V617F mutation, present in the
majority of patients with PV, seems to have a primary
role in the pathogenesis of myeloproliferative
neoplasms. The JAK2 gene maps to 9p24, so patients
carrying gains of 9p have an extra copy of the gene, in
its normal or mutated form, leading to a gain of
function.
The rearrangement here reported, der(9;18)(p10;q10),
is rarely detected in patients with PV, myelofibrosis,
essential thrombocythemia and therapy-related AML.
Some authors suggest that the simultaneous presence of
both JAK2 V617F mutation and this rearrangement
could define a subgroup of PV patients with the
proliferative phenotype of the disease, at high risk of
transformation into postpolycythemic myelofibrosis
and potentially acute myeloid leukemia.
We describe a new case of der(9;18)(p10;q10) detected
in a patient with AML evolved from post-polycythemic
myelofibrosis. The patient was diagnosed with PV in
1980 and died in 2010. He was in good health for
several years after diagnosis with bleeding treatment
and low dose aspirin, then he showed a progressive
worsening of anemia with liver enlargement and
splenomegaly. In February 2008 the diagnosis was of
myelofibrosis post PV in progression. In December
2008, when the leukemic transformation was evident,
the cytogenetic analysis on bone marrow aspirate found
the
unbalanced
translocation
leading
to
der(9;18)(p10;q10), with trisomy of the short arms of
chromosome 9 and monosomy of the short arms of
chromosome 18. FISH experiments with specific
alphoid centromeric probes for chromosome 9 and 18
showed both positive signals on the der(9). Subsequent
molecular analysis detected the presence of the JAK2
V617F mutation.
The patient here reported had a classical evolution of
the disease, after a very long polycythemic phase with a
noteworthy survival time likely correlated to the young
age of the patient when PV occurred. Because of the
absence of cytogenetic results at diagnosis and during
the polycythemic phase, we cannot fully evaluate the
significance of der(9;18)(p10;q10) in the natural history
of the disease before its evolution. Future reports could
make clear this not negligible aspect.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Ohyashiki K, Kodama A, Ohyashiki JH. Recurrent der(9;18) in
essential thrombocythemia with JAK2 V617F is highly linked to
myelofibrosis development. Cancer Genet Cytogenet. 2008
Oct;186(1):6-11
References
Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S,
Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg
AA. Gain of 9p in the pathogenesis of polycythemia vera.
Genes Chromosomes Cancer. 1998 Aug;22(4):321-4
Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin
JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement
der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas
Genet Cytogenet Oncol Haematol. April 2010. URL:
http://AtlasGeneticsOncology.org/Genes/der0918XuID100044.
html .
Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M,
Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis
following polycythemia vera. Cancer Genet Cytogenet. 2003
Jan 15;140(2):118-23
This article should be referenced as such:
Bacher U, Haferlach T, Schoch C. Gain of 9p due to an
unbalanced rearrangement der(9;18): a recurrent clonal
abnormality in chronic myeloproliferative disorders. Cancer
Genet Cytogenet. 2005 Jul 15;160(2):179-83
Cambosu F, Fogu G, Campus PM, Fozza C, Podda L,
Montella A, Longinotti M. Unbalanced rearrangement
der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with
AML following post-polycythemic myelofibrosis. Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(1):70-72.
Larsen TS, Hasselbalch HC, Pallisgaard N, Kerndrup GB. A
der(18)t(9;18)(p13;p11)
and
a
der(9;18)(p10;q10)
in
polycythemia vera associated with a hyperproliferative
phenotype in transformation to postpolycythemic myelofibrosis.
Cancer Genet Cytogenet. 2007 Jan 15;172(2):107-12
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
Cambosu F, et al.
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Educational Items Section
Weird animal genomes and sex chromosome
evolution
Jenny Graves
La Trobe University, Melbourne, Australia (JG) (Paper co-edited with the European Cytogeneticists
Association)
Published in Atlas Database: August 2011
Online updated version : http://AtlasGeneticsOncology.org/Educ/SexChromID30061EL.html
DOI: 10.4267/2042/47274
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Lactation complex: big changes in milk composition
between newborn and 3 months pouch young.
Premmies? Control?
There are 26 species of kangaroo.
We chose the tammar wallaby as our model kangaroo.
Small, easy to handle, most of the classic work on
marsupial physiology is done on this species.
Embryonic diapause: blastocyst goes into suspended
animation for up to 11 months.
Premature birth of underdeveloped Young: limb, organ
development still going on. Provides opportunities for
observation and manipulation of development that are
impossible in mouse.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Inter-island crosses like M. musculus x M. spretus
because they are very different.
- Lots of markers: microsatellite (variable numbers of
repeats).
- Have loads of phenotypic differences including in
reproductive characters like diapauses.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Mono and tammar differ by about 10 interchromosomal
rearrangements.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Cambosu F, et al.
Degeneration of the sex-specific element (Y or W)
from an original autosome, with examples of animal
species which exhibit this level of differentiation.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Nice examples of neofunctionalization (SRY, RBMY)
and subfunctionalization.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.
Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Cambosu F, et al.
This article should be referenced as such:
Graves J. Weird animal genomes and sex chromosome
evolution. Atlas Genet Cytogenet Oncol Haematol. 2012;
16(1):73-83.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation
in a patient with AML following post-polycythemic myelofibrosis
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1)
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Cambosu F, et al.