CELF2 (CUGBP, Elav-like family member 2)

2014-05-01   Satish Ramalingam , Shrikant Anant 

Department of Molecular, Integrative Physiology, Kansas University Medical Center, Kansas City, KS, USA

Identity

HGNC
LOCATION
10p14
LOCUSID
ALIAS
BRUNOL3,CELF-2,CUG-BP2,CUGBP2,ETR-3,ETR3,NAPOR
FUSION GENES

Abstract

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 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. 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.

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 N-terminal sequences (Ramalingam et al., 2008). There are totally 14 transcripts (splice variants) reported so far.

Proteins

Atlas Image
Figure 1. RRM position of CELF2 protein variants.

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.

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.

Implicated in

Entity name
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).
Entity name
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).
Entity name
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).
Entity name
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).
Entity name
Alzheimers 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).
Entity name
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).
Entity name
Ischemia
Note
The transient global ischemia induces the translational inhibition of genes with increased expression in normothermic mice. The authors 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).
Entity name
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).
Entity name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
115770822001Novel 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 et al
154829552004Expression profiling in spinal muscular atrophy reveals an RNA binding protein deficit.Anderson KN et al
127630132003Isolation and expression of Napor/CUG-BP2 in embryo development.Choi DK et al
156574172005Identification of putative new splicing targets for ETR-3 using sequences identified by systematic evolution of ligands by exponential enrichment.Faustino NA et al
126494962003Antagonistic regulation of alpha-actinin alternative splicing by CELF proteins and polypyrimidine tract binding protein.Gromak N et al
111583142001The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing.Ladd AN et al
152263692004Multiple domains control the subcellular localization and activity of ETR-3, a regulator of nuclear and cytoplasmic RNA processing events.Ladd AN et al
114147682001Genomic organization and isoform-specific tissue expression of human NAPOR (CUGBP2) as a candidate gene for familial arrhythmogenic right ventricular dysplasia.Li D et al
121109492002Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p.Lichtner P et al
98873311999Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy.Lu X et al
226606362012Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2.Miyazaki Y et al
150337802003CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury.Mukhopadhyay D et al
153588642004Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage.Murmu N et al
195590132009Transcriptional induction and translational inhibition of Arc and Cugbp2 in mice hippocampus after transient global ischemia under normothermic condition.Otsuka N et al
237953482012Reduced Expression of RNA Binding Protein CELF2, a Putative Tumor Suppressor Gene in Colon Cancer.Ramalingam S et al
213472862011RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells.Subramaniam D et al
173834272007Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation.Sureban SM et al
213793292011Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.Wijsman EM et al
178553672007Platelet-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 et al

Other Information

Locus ID:

NCBI: 10659
MIM: 602538
HGNC: 2550
Ensembl: ENSG00000048740

Variants:

dbSNP: 10659
ClinVar: 10659
TCGA: ENSG00000048740
COSMIC: CELF2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000048740ENST00000354897Q5VZZ6
ENSG00000048740ENST00000399850O95319
ENSG00000048740ENST00000416382O95319
ENSG00000048740ENST00000417956O95319
ENSG00000048740ENST00000542579E9PC62
ENSG00000048740ENST00000608830O95319
ENSG00000048740ENST00000609692V9GYD9
ENSG00000048740ENST00000609870V9GY47
ENSG00000048740ENST00000631460O95319
ENSG00000048740ENST00000631816A0A0J9YX66
ENSG00000048740ENST00000632065A0A0J9YXJ0
ENSG00000048740ENST00000632728O95319
ENSG00000048740ENST00000633077E9PC62
ENSG00000048740ENST00000633200A0A0J9YXK1
ENSG00000048740ENST00000636488A0A1B0GU44
ENSG00000048740ENST00000637215A0A1B0GUN8
ENSG00000048740ENST00000638035O95319

Expression (GTEx)

0
10
20
30
40
50
60

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
213793292011Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.99
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
173834272007Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation.42
271533972016Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation.35
182921812008Translation inhibition during cell cycle arrest and apoptosis: Mcl-1 is a novel target for RNA binding protein CUGBP2.30
264438492015Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation.29
214447162011Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2.24
214393712011Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing.21

Citation

Satish Ramalingam ; Shrikant Anant

CELF2 (CUGBP, Elav-like family member 2)

Atlas Genet Cytogenet Oncol Haematol. 2014-05-01

Online version: http://atlasgeneticsoncology.org/gene/52815/celf2