Download Gene Section CELF2 (CUGBP, Elav-like family member 2) in Oncology and Haematology

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CELF2 (CUGBP, Elav-like family member 2)
Satish Ramalingam, Shrikant Anant
Department of Molecular and Integrative Physiology, Kansas University Medical Center, Kansas City,
KS, USA (SR, SA)
Published in Atlas Database: May 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/CELF2ID52815ch10p14.html
DOI: 10.4267/2042/56292
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Location: 10p14
Note: Size: 331416 bases. Orientation: plus strand.
This gene is encoded by a gene located on
chromosome 10p13-p14 between Généthon
markers D10S547 and D10S223 (Li et al., 2001).
CELF2 belongs to the family of RNA binding
proteins implicated in mRNA splicing, editing,
stability and translation.
This gene is encoded in a single large gene
spanning over 159 kilo bases located on
chromosome 10 p13-p14 (between D10S547 and
D10S223).
This gene has 14 transcripts (splice variants) and
the 3 major splice variants have distinct exon 1.
This is an evolutionarily conserved ubiquitously
expressed protein. The members of the CELF
protein family contain two N-terminal RNA
recognition motif (RRM) domains and one Cterminal RRM domain, and a divergent segment of
160-230 amino acids between second and third
RRM domains. This divergent domain is unique to
CELF2 proteins and has been shown to contain one
or more activation molecules required for splicing
activity. CELF2 has been shown to bind to the
CUG and Au-rich element (ARE) in the target
mRNA and shown to be implicated in muscular
dystrophy and cancer.
Keywords
RNA binding protein, mRNA stability, splicing,
apoptosis,
translation
inhibition,
muscular
dystrophy, cancer
DNA/RNA
Description
The human CELF2 gene contains 14 exons
spanning over approximately 159 kb of the
genomic DNA.
Transcription
Alternative promoters usage of CELF2 gene results
in three transcript variants, where the variants 2 and
3 proteins have distinct exon 1 resulting in different
5' untranslated region (UTR) and have extended Nterminal sequences (Ramalingam et al., 2008).
There are totally 14 transcripts (splice variants)
reported so far.
Protein
Description
This is an evolutionarily conserved protein. The
members of the CELF protein family contain two
N-terminal RNA recognition motif (RRM) domains
and one C-terminal RRM domain, and a divergent
segment of 160-230 amino acids between second
and third RRM domains. This divergent domain is
unique to CELF2 proteins and has been shown to
contain one or more activation molecules required
for splicing activity (figure 1).
Identity
Other names: BRUNOL3, CUGBP2, ETR-3,
ETR3, NAPOR
HGNC (Hugo): CELF2
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(2)
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CELF2 (CUGBP, Elav-like family member 2)
Ramalingam S, Anant S
Figure 1. RRM position of CELF2 protein variants.
untranslated region (3' UTR) of the target mRNAs.
Upon binding to the AU-rich sequences in
cyclooxygenase-2 (COX-2) 3' UTR, CELF2
enhances the stability of COX-2 mRNA. However,
CUGBP2 binding also results in the inhibition of its
translation (Murmu et al., 2004). In our earlier
studies we have demonstrated that CELF2 can
interact with HuR, a key inducer of RNA stability
and translation, and competitively inhibit HuR
function (Sureban et al., 2007). Recently, platelet
derived growth factor was shown to enhance
CELF2 binding to COX-2 mRNA through
increased phosphorylation of a tyrosine residue at
position 39 in the protein (Xu et al., 2007). These
data suggest that posttranscriptional control
mechanisms are in place to modulate the CELF2
function as a regulator of stability and translation of
AU-rich transcripts.
Expression
CELF2 is a ubiquitously expressed protein.
According to the NCBI Entrez GEO profiles the
CELF2 is expressed in brain, heart, thymus, spleen,
bone, tongue, stomach, intestine, pancreas, liver,
breast, lung, kidney, testis, ovary, prostate, placenta
and skin. In addition, according to expression atlas
brain, bone marrow, heart, spleen, lymph node,
ovary and adipose tissue has more expression of
CELF2.
Localisation
CELF2 variant 1 is predominantly nuclear, while
variants 2 and 3 are predominantly cytoplasmic
(Ramalingam et al., 2008). CELF2 variant 1
accumulates in the cytoplasm following radiation
exposure (Mukhopadhyay et al., 2003a). The C
terminus of CELF2 transcript variant 1 is rich in
arginine and lysine residues 13 amino acids
(KRLKVQLKRSKND) 467 - 480, which is
common for NLS elements recognized by importin
proteins. Ladd and Cooper, has reported that the Cterminus of CELF2 contains a strong nuclear
localization signal overlapping the third RRM
(Ladd and Cooper, 2004). However, our
unpublished data suggests that nuclear localization
signal extends to the RNA recognition motif 1 and
2 domains. Finally, CELF2 has several leucine-rich
motifs that resembles nuclear export signals
recognized by the export protein CRM1.
Homology
According to GeneCards, the CELF2 has orthologs
in 72 species including much lower organisms such
as Danio rerio, Drosophila melanogaster,
Caenorhabditis elegans, Xenopus tropicalis and
Oryza sativa. Furthermore, in humans it has 6
paralogs from CELF1 to CELF6.
Mutations
Note
According to GeneCards, there is 7518 single
nucleotide polymorphism. However, Ensembl
reports that CELF2 has 7768 SNPs. In addition, the
Database of Genomic Variants shows that CELF2
has 18 structural variations.
Function
CELF2 is an RNA-binding protein implicated in the
regulation of several post-transcriptional events. It
has been shown to regulate pre-mRNA splicing
(Faustino and Cooper, 2005), mRNA editing
(Anant et al., 2001), mRNA translation and
stability. CELF2 has been shown to be involved in
alternative splicing of muscle specific genes
including exon 5 of cardiac troponin T (Ladd et al.,
2001), exon 11 of insulin receptor, intron 2 of
chloride channel 1, exons 5 and 21 of NMDAR-1,
and the muscle-specific exon of α-actinin (Gromak
et al., 2003). Another function for CELF2 relates to
its ability to bind to AU-rich sequences in 3'
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(2)
Implicated in
Colon cancer
Note
Putative tumor suppressor CELF2 expression is
consistently
reduced
during
neoplastic
transformation suggesting that it might play a
crucial role in tumor initiation and progression of
colon cancer. In addition, CELF2 has been shown
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CELF2 (CUGBP, Elav-like family member 2)
Ramalingam S, Anant S
muscular atrophy (Anderson et al., 2004). Spinal
and bulbar muscular atrophy (SBMA) is an
inherited neurodegenerative disorder caused by the
expansion of the polyglutamine (polyQ) tract of the
androgen receptor (AR-polyQ). It has been shown
that miR-196a enhanced the decay of the AR
mRNA by silencing CUGBP, Elav-like family
member 2 (CELF2). CELF2 shown to directly act
on AR mRNA and enhance the stability of AR
mRNA (Miyazaki et al., 2012). Myotonic
dystrophy (DM) is a neuromuscular disorder
associated with CTG triplet repeat expansion in the
myotonin protein kinase gene (DMPK). It has been
suggested that the expanded CUG repeats sequester
specific RNA-binding proteins and that such a
sequestration results in abnormal RNA processing
of several RNAs containing CUG repeats in
multiple tissues affected in patients with DM. One
of the members of the CUG-binding proteins,
CUG-BP, has been identified previously (Lu et al.,
1999).
to induce mitotic catastrophic cell death in colon
cancer (Ramalingam et al., 2012).
Pancreatic cancer
Note
Curcumin inhibits the pancreatic cancer growth by
inducing the expression of CELF2 thereby
regulating the levels of cyclooxygenase 2 and
vascular endothelial growth factor expression
(Subramaniam et al., 2011).
Breast cancer
Note
Breast cancer cells underwent apoptotic cell death
in response to radiation injury and this was reversed
by knockdown of CELF2 using specific siRNA
(Mukhopadhyay et al., 2003b).
Neuroblastoma
Note
Colchicine treatment of neuroblastoma cells
resulted in apoptotic cell death and CELF2 has been
shown to be involved in the process of cell death
(Li et al., 2001).
Development
Note
Overexpression of CELF2 by RNA microinjection
resulted in severe defects in nervous system and
gastrulation, suggesting the need for tight control of
napor gene regulation during embryo development
(Choi et al., 2003). CELF2 appears to be an
important factor for thymus development and is
therefore a candidate gene for the thymus
hypoplasia/aplasia seen in partial monosomy 10p
patients (Lichtner et al., 2002).
Alzheimer's disease
Note
It has been shown that variants in CUGBP2 on
chromosome 10p, are associated with AD in those
highest-risk APOE e4 homozygotes. This
interaction observation is replicated in independent
samples. CELF2 has one isoform that is expressed
predominantly in neurons, and identification of
such a new risk locus is important because of the
severity of AD (Wijsman et al., 2011).
References
Heart disease
Lu X, Timchenko NA, Timchenko LT. Cardiac elav-type
RNA-binding protein (ETR-3) binds to RNA CUG repeats
expanded in myotonic dystrophy. Hum Mol Genet. 1999
Jan;8(1):53-60
Note
Arrhythmogenic right ventricular dysplasia is the
most common cause of sudden cardiac death in the
young in Italy and the second most common cause
in the United States. One of the genes that was
mapped to this is in the vicinity of chromosome
10p12-p14 and it is CELF2 (Li et al., 2001).
Anant S, Henderson JO, Mukhopadhyay D, Navaratnam
N, Kennedy S, Min J, Davidson NO. Novel role for RNAbinding protein CUGBP2 in mammalian RNA editing.
CUGBP2 modulates C to U editing of apolipoprotein B
mRNA by interacting with apobec-1 and ACF, the apobec1 complementation factor. J Biol Chem. 2001 Dec
14;276(50):47338-51
Ischemia
Note
The transient global ischemia induces the
translational inhibition of genes with increased
expression in normothermic mice. The author's
correlate the translational inhibition with CELF2
expression and this might play an important role in
the progress of neuronal injury after transient global
ischemia (Otsuka et al., 2009).
Ladd AN, Charlet N, Cooper TA. The CELF family of RNA
binding proteins is implicated in cell-specific and
developmentally regulated alternative splicing. Mol Cell
Biol. 2001 Feb;21(4):1285-96
Li D, Bachinski LL, Roberts R. Genomic organization and
isoform-specific tissue expression of human NAPOR
(CUGBP2) as a candidate gene for familial arrhythmogenic
right ventricular dysplasia. Genomics. 2001 Jun
15;74(3):396-401
Atrophy
Lichtner P, Attié-Bitach T, Schuffenhauer S, Henwood J,
Bouvagnet P, Scambler PJ, Meitinger T, Vekemans M.
Expression and mutation analysis of BRUNOL3, a
candidate gene for heart and thymus developmental
defects associated with partial monosomy 10p. J Mol Med
(Berl). 2002 Jul;80(7):431-42
Note
The differential expression of CELF2 has been
confirmed with real-time RT-PCR in spinal cord
and muscle of three different models of spinal
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(2)
95
CELF2 (CUGBP, Elav-like family member 2)
Ramalingam S, Anant S
Choi DK, Yoo KW, Hong SK, Rhee M, Sakaki Y, Kim CH.
Isolation and expression of Napor/CUG-BP2 in embryo
development. Biochem Biophys Res Commun. 2003 Jun
6;305(3):448-54
growth factor-induced stabilization of cyclooxygenase 2
mRNA in rat smooth muscle cells requires the c-Src family
of protein-tyrosine kinases. J Biol Chem. 2007 Nov
9;282(45):32699-709
Gromak N, Matlin AJ, Cooper TA, Smith CW. Antagonistic
regulation of alpha-actinin alternative splicing by CELF
proteins and polypyrimidine tract binding protein. RNA.
2003 Apr;9(4):443-56
Ramalingam S, Natarajan G, Schafer C, Subramaniam D,
May R, Ramachandran I, Queimado L, Houchen CW,
Anant S. Novel intestinal splice variants of RNA-binding
protein CUGBP2: isoform-specific effects on mitotic
catastrophe. Am J Physiol Gastrointest Liver Physiol. 2008
Apr;294(4):G971-81
Mukhopadhyay D, Houchen CW, Kennedy S, Dieckgraefe
BK, Anant S. Coupled mRNA stabilization and translational
silencing of cyclooxygenase-2 by a novel RNA binding
protein, CUGBP2. Mol Cell. 2003a Jan;11(1):113-26
Otsuka N, Tsuritani K, Sakurai T, Kato K, Matoba R, Itoh J,
Okuyama S, Yamada K, Yoneda Y. Transcriptional
induction and translational inhibition of Arc and Cugbp2 in
mice hippocampus after transient global ischemia under
normothermic condition. Brain Res. 2009 Sep 1;1287:13645
Mukhopadhyay D, Jung J, Murmu N, Houchen CW,
Dieckgraefe BK, Anant S. CUGBP2 plays a critical role in
apoptosis of breast cancer cells in response to genotoxic
injury. Ann N Y Acad Sci. 2003b Dec;1010:504-9
Subramaniam D, Ramalingam S, Linehan DC, Dieckgraefe
BK, Postier RG, Houchen CW, Jensen RA, Anant S. RNA
binding protein CUGBP2/CELF2 mediates curcumininduced mitotic catastrophe of pancreatic cancer cells.
PLoS One. 2011 Feb 11;6(2):e16958
Anderson KN, Baban D, Oliver PL, Potter A, Davies KE.
Expression profiling in spinal muscular atrophy reveals an
RNA binding protein deficit. Neuromuscul Disord. 2004
Nov;14(11):711-22
Ladd AN, Cooper TA. Multiple domains control the
subcellular localization and activity of ETR-3, a regulator of
nuclear and cytoplasmic RNA processing events. J Cell
Sci. 2004 Jul 15;117(Pt 16):3519-29
Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber
KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia
R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM,
Mayeux R. Genome-wide association of familial late-onset
Alzheimer's disease replicates BIN1 and CLU and
nominates CUGBP2 in interaction with APOE. PLoS
Genet. 2011 Feb;7(2):e1001308
Murmu N, Jung J, Mukhopadhyay D, Houchen CW, Riehl
TE, Stenson WF, Morrison AR, Arumugam T, Dieckgraefe
BK, Anant S. Dynamic antagonism between RNA-binding
protein
CUGBP2
and
cyclooxygenase-2-mediated
prostaglandin E2 in radiation damage. Proc Natl Acad Sci
U S A. 2004 Sep 21;101(38):13873-8
Miyazaki Y, Adachi H, Katsuno M, Minamiyama M, Jiang
YM, Huang Z, Doi H, Matsumoto S, Kondo N, Iida M,
Tohnai G, Tanaka F, Muramatsu S, Sobue G. Viral
delivery of miR-196a ameliorates the SBMA phenotype via
the silencing of CELF2. Nat Med. 2012 Jul;18(7):1136-41
Faustino NA, Cooper TA. Identification of putative new
splicing targets for ETR-3 using sequences identified by
systematic evolution of ligands by exponential enrichment.
Mol Cell Biol. 2005 Feb;25(3):879-87
Ramalingam S, Ramamoorthy P, Subramaniam D, Anant
S. Reduced Expression of RNA Binding Protein CELF2, a
Putative Tumor Suppressor Gene in Colon Cancer.
Immunogastroenterology. 2012;1(1):27-33
Sureban SM, Murmu N, Rodriguez P, May R, Maheshwari
R, Dieckgraefe BK, Houchen CW, Anant S. Functional
antagonism between RNA binding proteins HuR and
CUGBP2 determines the fate of COX-2 mRNA translation.
Gastroenterology. 2007 Mar;132(3):1055-65
This article should be referenced as such:
Ramalingam S, Anant S. CELF2 (CUGBP, Elav-like family
member 2). Atlas Genet Cytogenet Oncol Haematol. 2015;
19(2):93-96.
Xu K, Kitchen CM, Shu HK, Murphy TJ. Platelet-derived
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(2)
96