Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

Verma, Sunil Kumar; Deshmukh, Vaibhav; Liu, Patrick; Nutter, Curtis A.; Espejo, Rosario; Hung, Ming‐Lung; Wang, Guey-Shin; Yeo, G; Kuyumcu‐Martinez, Muge N.

doi:10.1074/jbc.m113.507426

Cited by 55 publications

(106 citation statements)

References 85 publications

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“…Finally, misregulation or misexpression of both CELF2 and RBFOX2 have been implicated as contributors to human disease including cancer, muscular dystrophies, heart failure, and Type 1 diabetes (Kuyumcu-Martinez et al 2007;Cooper et al 2009;Verma et al 2013;Nutter et al 2016). Our finding of mutual antagonism between these proteins suggests that disease-relevant splicing attributed previously to CELF2 or RBFOX2 may also be impacted by altered expression of the other.…”

Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Humentioning

confidence: 55%

“…RBFOX2 has been shown to be dysregulated in the hearts of diabetic patients and a mouse model of Type I diabetes (T1D), where it forms a dominant negative version of the protein, leading to a number of splicing changes (Nutter et al 2016). CELF1 has also been shown to be up-regulated in diabetic hearts via PKC signaling (Kuyumcu- Martinez et al 2007;Verma et al 2013), but the global consequences of this have not been examined. By analyzing public data, we observe not only the previous finding that RBFOX2 depletion largely mirrors changes induced in a mouse model of T1D (r = 0.44) (Fig.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

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Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

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Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution.

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Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Humentioning

confidence: 55%

Section: Wwwgenomeorgmentioning

confidence: 99%

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

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“…CUGBP1 has been reported to mediate alternative splicing of the insulin receptor [27] and to contribute to insulin resistance [28]. Verma et al showed that CUGBP1 is upregulated in the hearts of diabetic mice [29]. A recent genome-wide association study analysis suggested that genetic variation at the CUGBP1 locus is associated with obesity [30].…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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Aims/hypothesis CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain-and loss-of-function experiments and to further decipher the underlying molecular mechanisms. Methods A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose-and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose-and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. Conclusions/interpretation We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

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“…Also, we found CELF1 phosphorylation at serine 28 in malignant T cells but not in resting or activated normal T cells, indicating that the site of phosphorylation of CELF1 differs in normal and malignant T cells. PKC α/βII-dependent phosphorylation of CELF1 at serine 28 is involved in murine heart development (Verma et al 2013), but the role of phosphorylation of CELF1 at serine 28 in T cells has not been evaluated. Finding that CELF1 was phosphorylated at S28 in malignant T cells, but not in activated normal T cells suggests that different kinases that phosphorylate CELF1 at serine 28, or other positions, are expressed or activated in malignant T cells.…”

Section: Discussionmentioning

confidence: 99%

Altered CELF1 binding to target transcripts in malignant T cells

Bohjanen

Moua

Guo

et al. 2015

RNA

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The RNA-binding protein, CELF1, binds to a regulatory sequence known as the GU-rich element (GRE) and controls a network of mRNA transcripts that regulate cellular activation, proliferation, and apoptosis. We performed immunoprecipitation using an anti-CELF1 antibody, followed by identification of copurified transcripts using microarrays. We found that CELF1 is bound to a distinct set of target transcripts in the H9 and Jurkat malignant T-cell lines, compared with primary human T cells. CELF1 was not phosphorylated in resting normal T cells, but in malignant T cells, phosphorylation of CELF1 correlated with its inability to bind to GRE-containing mRNAs that served as CELF1 targets in normal T cells. Lack of binding by CELF1 to these mRNAs in malignant T cells correlated with stabilization and increased expression of these transcripts. Several of these GRE-containing transcripts that encode regulators of cell growth were also stabilized and up-regulated in primary tumor cells from patients with T-cell acute lymphoblastic leukemia. Interestingly, transcripts encoding numerous suppressors of cell proliferation that served as targets of CELF1 in malignant T cells, but not normal T cells, exhibited accelerated degradation and reduced expression in malignant compared with normal T cells, consistent with the known function of CELF1 to mediate degradation of bound transcripts. Overall, CELF1 dysfunction in malignant T cells led to the up-regulation of a subset of GRE-containing transcripts that promote cell growth and down-regulation of another subset that suppress cell growth, producing a net effect that would drive a malignant phenotype.

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Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

Cited by 55 publications

References 85 publications

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Altered CELF1 binding to target transcripts in malignant T cells

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