Alternative titles; symbols
HGNC Approved Gene Symbol: CELF1
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,465,937-47,565,539 (from NCBI)
Members of the CELF family, such as CELF1, play various roles in cotranscriptional and posttranscriptional RNA processing. All CELF proteins appear to affect pre-mRNA splicing, but individual CELFs have divergent roles in regulating mRNA stability and translation (summary by Wagnon et al., 2012).
An unstable CTG triplet repeat expansion in the DMPK gene (605377) is responsible for myotonic dystrophy (DM1; 160900). To detect proteins that bind to CTG triplet repeats, Timchenko et al. (1996) performed bandshift analysis using as probes double-stranded DNA fragments having CTG repeats and single-stranded oligonucleotides having CTG repeats or RNA CUG repeats. The proteins were derived from nuclear and cytoplasmic extracts of HeLa cells, fibroblasts, and myotubes. Proteins binding to the double-stranded DNA repeat were inhibited by the nonlabeled repeat but not by a nonspecific DNA fragment. Another protein binding to the single-stranded CTG probe and the RNA CUG probe was inhibited by nonlabeled CTG(8) and CUG(8) repeats. The protein binding only to the RNA repeat (CUG)8 was inhibited by nonlabeled (CUG)8 but not by nonlabeled single- or double-stranded CTG repeats. Furthermore, the protein, designated CUG-binding protein (CUGBP) by the authors, exhibited no binding to an RNA oligonucleotide of triplet repeats of the same length but having a different sequence, CGG. The CUG-binding protein was localized to the cytoplasm, whereas double-stranded DNA binding proteins were localized to the nuclear extract. Thus, Timchenko et al. (1996) concluded that several trinucleotide-binding proteins exist and their specificity is determined by the triplet sequence.
CTG trinucleotide repeats encode CUG repeat regions in the corresponding mRNAs. Timchenko et al. (1996) identified 2 proteins, termed CUGBP1 and CUGBP2, that bind specifically to CUG repeats in RNA. They suggested that these 2 proteins, with masses of 49 kD and 51 kD, respectively, are isoforms encoded by the same gene. Timchenko et al. (1996) cloned a gene, termed NAB50 by them, based on the interaction between its protein product and the yeast Nab2 protein. The authors stated that the NAB50 gene encodes the CUGBP1 and CUGBP2 proteins because anti-Nab50 antibodies crossreacted with both CUGBP isoforms. The gene predicts a 482-amino acid protein with a calculated molecular mass of 52 kD. The predicted protein contains 3 RNA-binding domains and is homologous to the hnRNPs.
Good et al. (2000) identified CUGBP1 as BRUNOL2, a member of a human gene family related to the transcriptional regulator 'Bruno' of Drosophila. By PCR, they cloned BRUNOL2 from a brain cDNA library. The deduced protein contains 2 N-terminal RNA recognition motifs (RRMs), a long linker region, and a C-terminal RRM. BRUNOL2 and BRUNOL3 (CUGBP2; 602538) share 80% amino acid identity overall and more than 92% identity in their RRMs. Good et al. (2000) determined that the BRUNOL2 cDNA and the CUGBP1 cDNA reported by Timchenko et al. (1996) differ in their 3-prime UTRs due to alternative splicing. Good et al. (2000) also identified a BRUNOL2 splice variant with an additional 12 bp, resulting in a 4-amino acid insertion in the linker region. Northern blot analysis detected variable expression of 3 major BRUNOL2 transcripts of about 9.5, 7.5, and 2.4 kb in all tissues examined.
Using RNA dot blot analysis, Ladd et al. (2004) confirmed ubiquitous expression of CUGBP1.
Timchenko et al. (1996) showed that the NAB50 gene product bound the CUG repeat region of DMPK.
Using 2 biologic systems with reduced DMPK levels, a homozygous DM patient and DMPK knockout mice, Roberts et al. (1997) demonstrated that the intracellular distribution of CUGBP isoforms was altered in the absence of DMPK. DMPK phosphorylated the CUGBP protein in vitro, suggesting regulation of nuclear CUGBP localization via phosphorylation.
Using ultraviolet light crosslinking and gel mobility shift assays, Good et al. (2000) showed that BRUNOL2 bound RNA containing a BRUNO response element (BRE).
Dudaronek et al. (2007) showed that Ifnb (147720) induced expression of Lip, a truncated, dominant-negative isoform of Cebpb (189965), and suppressed active simian immunodeficiency virus (SIV) replication in macaque macrophages. In a human monocyte cell line, IFNB induced phosphorylation of CUGBP1 and formation of CUGBP1-CEBPB mRNA complexes. Depletion of Cugbp1 in macaque macrophages via small interfering RNA showed that Cugbp1 was required for Ifnb-mediated induction of Lip and for Ifnb-mediated suppression of SIV replication. Dudaronek et al. (2007) concluded that CUGBP1 is a downstream effector of IFNB signaling in primary macrophages that plays an important role in innate immune responses controlling acute human immunodeficiency virus (HIV) or SIV replication in brain.
A transgenic fly model of fragile X-associated tremor/ataxia syndrome (FXTAS; 300623) in which the 5-prime UTR of human FMR1 (309550) containing 90 CGG repeats is expressed specifically in the eye results in disorganized ommatidia, depigmentation, and progressive loss of photoreceptor neurons. Sofola et al. (2007) found that overexpression of human CUGBP1 suppressed the neurodegenerative eye phenotype in transgenic flies. CUGBP1 did not interact directly with the CGG repeats, but did so via HNRNPA2B1 (600124). Expression of the A2 isoform of human HNRNPA2B1, or the Drosophila orthologs, also suppressed the eye phenotype of FXTAS flies. CUGBP1 did not interact with other HNRNPs examined.
Tang et al. (2012) observed altered splicing of the calcium channel subunit CAV1.1 (CACNA1S; 114208) in muscle of patients with DM1 and DM2 (602668) compared with normal adult muscle and muscle of patients with facioscapulohumeral muscular dystrophy (FSHD; see 158900). A significant fraction of CAV1.1 transcripts in DM1 and DM2 muscle showed skipping of exon 29, which represents a fetal splicing pattern. Forced exclusion of exon 29 in normal mouse skeletal muscle altered channel gating properties and increased current density and peak electrically evoked calcium transient magnitude. Downregulation of Mbnl1 (606516) in mouse cardiac muscle or overexpression of Cugbp1 in mouse tibialis anterior muscle enhanced skipping of exon 29, suggesting that these splicing factors may be involved in the CAV1.1 splicing defect in myotonic dystrophy.
By genomic sequence analysis, Good et al. (2000) mapped the CUGBP1 gene to chromosome 11p11.
Wang et al. (2007) generated an inducible and heart-specific mouse model of DM1 that expressed expanded human DMPK CUG-repeat RNA and recapitulated pathologic features of the human disorder, including dilated cardiomyopathy, arrhythmias, and systolic and diastolic dysfunction. The mice also showed misregulation of developmental alternative splicing transitions, including the Tnnt2 (191045) and Fxr1 (600819) genes. All died of heart failure within 2 weeks. Immunohistochemical studies showed increased CUGBP1 protein levels specifically in nuclei containing foci of DMPK CUG-repeat RNA. A time-course study showed that increased CUGBP1 co-occurred within hours of induced expression of the CUG repeat and coincided with reversion to embryonic splicing patterns. The results indicated that increased CUGBP1 is a specific and early event of DM1 pathogenesis and represents a primary response to expression of DMPK CUG-repeat mutant RNA.
Koshelev et al. (2010) expressed human CUGBP1 in adult mouse heart. Upregulation of CUGBP1 was sufficient to reproduce molecular, histopathologic, and functional changes observed in a DM1 mouse model that expressed expanded CUG RNA repeats (Wang et al., 2007) as well as in individuals with DM1. The authors concluded that CUGBP1 upregulation plays an important role in DM1 pathogenesis.
By inducing expression of human CUGBP1 in adult skeletal muscle of transgenic mice, Ward et al. (2010) showed that the pathogenic features of DM1 could be explained by upregulated CUGBP1 expression. Within weeks of induction of CUGBP1 expression, transgenic mice exhibited impaired movement, reduced muscle function, abnormal gait, and reduced total body weight compared with uninduced controls. Histologic analysis of transgenic muscle overexpressing CUGBP1 revealed centrally located nuclei, myofiber degeneration with inflammatory infiltrate, and pyknotic nuclear clumps. RT-PCR analysis revealed reversion to embryonic splicing patterns in several genes in transgenic muscle overexpressing CUGBP1. Ward et al. (2010) concluded that CUGBP1 has a major role in DM1 skeletal muscle pathogenesis.
Using an inducible toxic RNA transgene mouse model of DM1, Kim et al. (2014) found that wildtype mice expressing toxic RNA showed Celf1 overexpression, predominantly in muscles with the most severe histopathology. Similar findings were observed in DM1 patients. In the absence of toxic RNA expression, Celf1 -/- mice showed muscle weakness in treadmill and grip-strength tests and developed cataracts, but they did not show obvious histopathology in skeletal muscle. Celf1 +/- mice showed a milder phenotype. Following induced expression of toxic RNA, Celf1 -/- mice showed no further decline, and absence of Celf1 led to better muscle histology. Neither Celf-/- nor Celf +/- mice were protected from toxic RNA-induced RNA splicing defects or cardiac conduction defects and myotonia.
Dudaronek, J. M., Barber, S. A., Clements, J. E. CUGBP1 is required for IFN-beta-mediated induction of dominant-negative CEBP-beta and suppression of SIV replication in macrophages. J. Immun. 179: 7262-7269, 2007. [PubMed: 18025168] [Full Text: https://doi.org/10.4049/jimmunol.179.11.7262]
Good, P. J., Chen, Q., Warner, S. J., Herring, D. C. A family of human RNA-binding proteins related to the Drosophila Bruno transcriptional regulator. J. Biol. Chem. 275: 28583-28592, 2000. [PubMed: 10893231] [Full Text: https://doi.org/10.1074/jbc.M003083200]
Kim, Y. K., Mandal, M., Yadava, R. S., Paillard, L., Mahadevan, M. S. Evaluating the effects of CELF1 deficiency in a mouse model of RNA toxicity. Hum. Molec. Genet. 23: 293-302, 2014. [PubMed: 24001600] [Full Text: https://doi.org/10.1093/hmg/ddt419]
Koshelev, M., Sarma, S., Price, R. E., Wehrens, X. H. T., Cooper, T. A. Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum. Molec. Genet. 19: 1066-1075, 2010. [PubMed: 20051426] [Full Text: https://doi.org/10.1093/hmg/ddp570]
Ladd, A. N., Nguyen, N. H., Malhotra, K., Cooper, T. A. CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific splicing enhancer-dependent alternative splicing. J. Biol. Chem. 279: 17756-17764, 2004. [PubMed: 14761971] [Full Text: https://doi.org/10.1074/jbc.M310687200]
Roberts, R., Timchenko, N. A., Miller, J. W., Reddy, S., Caskey, C. T., Swanson, M. S., Timchenko, L. T. Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice. Proc. Nat. Acad. Sci. 94: 13221-13226, 1997. [PubMed: 9371827] [Full Text: https://doi.org/10.1073/pnas.94.24.13221]
Sofola, O. A., Jin, P., Qin, Y., Duan, R., Liu, H., de Haro, M., Nelson, D. L., Botas, J. RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55: 565-571, 2007. [PubMed: 17698010] [Full Text: https://doi.org/10.1016/j.neuron.2007.07.021]
Tang, Z. Z., Yarotskyy, V., Wei, L., Sobczak, K., Nakamori, M., Eichinger, K., Moxley, R. T., Dirksen, R. T., Thornton, C. A. Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of CaV1.1 calcium channel. Hum. Molec. Genet. 21: 1312-1324, 2012. [PubMed: 22140091] [Full Text: https://doi.org/10.1093/hmg/ddr568]
Timchenko, L. T., Miller, J. W., Timchenko, N. A., DeVore, D. R., Datar, K. V., Lin, L., Roberts, R., Caskey, C. T., Swanson, M. S. Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res. 24: 4407-4414, 1996. [PubMed: 8948631] [Full Text: https://doi.org/10.1093/nar/24.22.4407]
Timchenko, L. T., Timchenko, N. A., Caskey, C. T., Roberts, R. Novel proteins with binding specificity for DNA CTG repeats and RNA CUG repeats: implications for myotonic dystrophy. Hum. Molec. Genet. 5: 115-121, 1996. [PubMed: 8789448] [Full Text: https://doi.org/10.1093/hmg/5.1.115]
Wagnon, J. L., Briese, M., Sun, W., Mahaffey, C. L., Curk, T., Rot, G., Ule, J., Frankel, W. N. CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function. PLoS Genet. 8: e1003067, 2012. Note: Electronic Article. [PubMed: 23209433] [Full Text: https://doi.org/10.1371/journal.pgen.1003067]
Wang, G.-S., Kearney, D. L., De Biasi, M., Taffet, G., Cooper, T. A. Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J. Clin. Invest. 117: 2802-2811, 2007. [PubMed: 17823658] [Full Text: https://doi.org/10.1172/JCI32308]
Ward, A. J., Rimer, M., Killian, J. M., Dowling, J. J., Cooper, T. A. CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum. Molec. Genet. 19: 3614-3622, 2010. [PubMed: 20603324] [Full Text: https://doi.org/10.1093/hmg/ddq277]