Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

Sun, Shuying; Zuo, Zhuang; Fregoso, Oliver I.; Krainer, Adrian R.

doi:10.1261/rna.030486.111

Cited by 89 publications

(101 citation statements)

References 46 publications

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“…RBFOX proteins have a single RRM, highly homologous among the three paralogs, and their binding sites are exceptionally highly conserved in sequence (UGCAUG) and position across vertebrate evolution (Sun et al 2012). Mutations or deletions in RBFOX1 and RBFOX3 are found in epilepsy patients (Bhalla et al 2004;Lal et al 2013a,b), whereas copy-number variations in RBFOX1 are associated with autism spectrum disorders and spinocerebellar ataxias (Bill et al 2013;Weyn-Vanhentenryck et al 2014).…”

Section: Rbfox2-rna Binding Protein Fox-2 Homologmentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

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226

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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Section: Rbfox2-rna Binding Protein Fox-2 Homologmentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

Self Cite

226

247

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“…Interestingly, more recent work has shown cooperativity between MBNL and RBFOX proteins in iPSC reprogramming and muscle differentiation as well as in a myotonic dystrophy model (Venables et al 2013;Klinck et al 2014). RBFOX proteins have also been shown to regulate splicing in cooperation with other individual RBPs such as ESRP (Dittmar et al 2012), PTBP , and HNRNPH1 (Sun et al 2011). In particular, recent work has demonstrated that RBFOX proteins in mammals often function through the activity of a large multiprotein assembly that influences the binding and activity of RBFOX (LASR) ).…”

Section: Cooperation and Competition With Other Rbps Is A Common Featmentioning

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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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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“…Strikingly, the set of ERG interactors identified in our Y2H screen also included RNA-binding Fox-1 (RBFOX1 or A2BP1) and RNA-binding protein with multiple splicing (RBPMS or Hermes), two RBPs with canonical RNA-recognition motifs 34,35 (Supplementary Table 1). Whereas RBFOX proteins are wellcharacterized splicing factors, the role of RBPMS in mRNA processing remains unclear 36,37 . From these findings, we hypothesized that ERG might be recruited to specific mRNAs through its interaction with RBPs including RBPMS.…”

Section: Erg Is Recruited To Mrna Via Its Interaction With Rbpsmentioning

confidence: 99%

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Rambout

Detiffe

Bruyr

et al. 2016

Nat Struct Mol Biol

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nature structural & molecular biology advance online publication a r t i c l e sAlthough undisputable evidence has clearly demonstrated that the nuclear steps of mRNA processing are mechanistically linked to transcription, a conceptual evolution in gene regulation has come with the realization that transcription might also be functionally connected to more remote processes occurring in the cytoplasm, such as mRNA decay 1,2 . Cytoplasmic mRNA decay is initiated by deadenylation, a rate-limiting event during which the poly(A) tail of the transcript is trimmed off by the CCR4-NOT complex, the main deadenylation machinery in eukaryotes 3 . The degradation of specific mRNAs, a key process in the regulation of eukaryotic gene expression, is achieved through the recruitment of the CCR4-NOT complex by sequence-specific RNA-binding proteins (RBPs) or by the microRNA machinery 3,4 . Poly(A)-shortened mRNAs, along with factors involved in the deadenylation, decapping and mRNA-degradation machineries, accumulate in microscopic mRNA-protein complex (mRNP) aggregates called processing bodies (PBs) 5 .The idea of coupling between mRNA synthesis and degradation has recently emerged. Genome-wide expression studies in yeast have shown that mRNA synthesis and decay are mechanistically and functionally coordinated, thus supporting the existence of common molecular effectors [6][7][8][9] . In particular, the CCR4-NOT deadenylation complex was first described as a transcriptional regulator and has been implicated in initiation and elongation by RNA polymerase II 10,11 . More surprisingly, it has also been shown that degradation of yeast mRNAs is determined by cis-acting sequence elements in promoters 12,13 . These findings have led to the concept of mRNA imprinting, in which sequence-specific DNA-binding factors might orchestrate mRNA synthesis and decay. This decay would occur via loading of factors regulating cytoplasmic mRNA degradation onto the transcribing mRNA 14 . However, the identity of these DNA-binding mRNA coordinators is still obscure, and it remains to be tested whether such coupling between transcription and decay also exists in higher eukaryotes. E26 (Ets) proteins, a family of 28 helix-loop-helix transcription factors (TFs) in metazoans, are characterized by a highly conserved DNA-binding ETS domain 15 . Through this domain, Ets factors bind specific gene promoters and act as key regulators in many biological processes including cellular proliferation, apoptosis, differentiation and survival 16 . ERG, FLI1 and the more structurally divergent FEV compose the Erg subfamily of Ets factors and have been identified as driving factors in prostate cancer, Ewing's tumors and leukemias 15,17 . Using ERG as a paradigm, we sought to investigate the possibility that eukaryotic transcription factors might be directly involved in cytoplasmic mRNA decay. We demonstrate that ERG triggers degradation of mRNAs connected to Aurora signaling by recruiting RBPs and the CCR4-NOT deadenylation complex and that this activity is important fo...

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Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2

Cited by 89 publications

References 46 publications

Splicing-factor alterations in cancers

Splicing-factor alterations in cancers

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

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