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| Figure 1. RRM position of CELF2 protein variants. |
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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). |
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 C-terminus 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 However, our unpublished data suggests that nuclear localization signal extends to the RNA recognition motif 1 and 2 domains.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. |
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' 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. |
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. |
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Entity | 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 to induce mitotic catastrophic cell death in colon cancer (Ramalingam et al., 2012). |
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Entity | 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). |
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Entity | 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). |
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Entity | 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). |
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Entity | 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). |
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Entity | Heart disease |
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). |
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Entity | 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). |
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Entity | Atrophy |
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 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). |
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Entity | 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). |
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Novel role for RNA-binding protein CUGBP2 in mammalian RNA editing. CUGBP2 modulates C to U editing of apolipoprotein B mRNA by interacting with apobec-1 and ACF, the apobec-1 complementation factor. |
Anant S, Henderson JO, Mukhopadhyay D, Navaratnam N, Kennedy S, Min J, Davidson NO. |
J Biol Chem. 2001 Dec 14;276(50):47338-51. Epub 2001 Sep 27. |
PMID 11577082 |
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Expression profiling in spinal muscular atrophy reveals an RNA binding protein deficit. |
Anderson KN, Baban D, Oliver PL, Potter A, Davies KE. |
Neuromuscul Disord. 2004 Nov;14(11):711-22. |
PMID 15482955 |
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Isolation and expression of Napor/CUG-BP2 in embryo development. |
Choi DK, Yoo KW, Hong SK, Rhee M, Sakaki Y, Kim CH. |
Biochem Biophys Res Commun. 2003 Jun 6;305(3):448-54. |
PMID 12763013 |
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Identification of putative new splicing targets for ETR-3 using sequences identified by systematic evolution of ligands by exponential enrichment. |
Faustino NA, Cooper TA. |
Mol Cell Biol. 2005 Feb;25(3):879-87. |
PMID 15657417 |
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Antagonistic regulation of alpha-actinin alternative splicing by CELF proteins and polypyrimidine tract binding protein. |
Gromak N, Matlin AJ, Cooper TA, Smith CW. |
RNA. 2003 Apr;9(4):443-56. |
PMID 12649496 |
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The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. |
Ladd AN, Charlet N, Cooper TA. |
Mol Cell Biol. 2001 Feb;21(4):1285-96. |
PMID 11158314 |
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Multiple domains control the subcellular localization and activity of ETR-3, a regulator of nuclear and cytoplasmic RNA processing events. |
Ladd AN, Cooper TA. |
J Cell Sci. 2004 Jul 15;117(Pt 16):3519-29. Epub 2004 Jun 29. |
PMID 15226369 |
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Genomic organization and isoform-specific tissue expression of human NAPOR (CUGBP2) as a candidate gene for familial arrhythmogenic right ventricular dysplasia. |
Li D, Bachinski LL, Roberts R. |
Genomics. 2001 Jun 15;74(3):396-401. |
PMID 11414768 |
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Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. |
Lichtner P, Attie-Bitach T, Schuffenhauer S, Henwood J, Bouvagnet P, Scambler PJ, Meitinger T, Vekemans M. |
J Mol Med (Berl). 2002 Jul;80(7):431-42. Epub 2002 Apr 4. |
PMID 12110949 |
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Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. |
Lu X, Timchenko NA, Timchenko LT. |
Hum Mol Genet. 1999 Jan;8(1):53-60. |
PMID 9887331 |
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Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. |
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. |
Nat Med. 2012 Jul;18(7):1136-41. doi: 10.1038/nm.2791. |
PMID 22660636 |
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CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury. |
Mukhopadhyay D, Jung J, Murmu N, Houchen CW, Dieckgraefe BK, Anant S. |
Ann N Y Acad Sci. 2003b Dec;1010:504-9. |
PMID 15033780 |
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Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage. |
Murmu N, Jung J, Mukhopadhyay D, Houchen CW, Riehl TE, Stenson WF, Morrison AR, Arumugam T, Dieckgraefe BK, Anant S. |
Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13873-8. Epub 2004 Sep 9. |
PMID 15358864 |
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Transcriptional induction and translational inhibition of Arc and Cugbp2 in mice hippocampus after transient global ischemia under normothermic condition. |
Otsuka N, Tsuritani K, Sakurai T, Kato K, Matoba R, Itoh J, Okuyama S, Yamada K, Yoneda Y. |
Brain Res. 2009 Sep 1;1287:136-45. doi: 10.1016/j.brainres.2009.06.050. Epub 2009 Jun 24. |
PMID 19559013 |
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Reduced Expression of RNA Binding Protein CELF2, a Putative Tumor Suppressor Gene in Colon Cancer. |
Ramalingam S, Ramamoorthy P, Subramaniam D, Anant S. |
Immunogastroenterology. 2012;1(1):27-33. |
PMID 23795348 |
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RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. |
Subramaniam D, Ramalingam S, Linehan DC, Dieckgraefe BK, Postier RG, Houchen CW, Jensen RA, Anant S. |
PLoS One. 2011 Feb 11;6(2):e16958. doi: 10.1371/journal.pone.0016958. |
PMID 21347286 |
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Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation. |
Sureban SM, Murmu N, Rodriguez P, May R, Maheshwari R, Dieckgraefe BK, Houchen CW, Anant S. |
Gastroenterology. 2007 Mar;132(3):1055-65. Epub 2006 Dec 19. |
PMID 17383427 |
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Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. |
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; NIA-LOAD/NCRAD Family Study Group. |
PLoS Genet. 2011 Feb;7(2):e1001308. doi: 10.1371/journal.pgen.1001308. Epub 2011 Feb 17. |
PMID 21379329 |
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Platelet-derived growth factor-induced stabilization of cyclooxygenase 2 mRNA in rat smooth muscle cells requires the c-Src family of protein-tyrosine kinases. |
Xu K, Kitchen CM, Shu HK, Murphy TJ. |
J Biol Chem. 2007 Nov 9;282(45):32699-709. Epub 2007 Sep 12. |
PMID 17855367 |
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