The transcription factor FBI-1 inhibits SAM68-mediated BCL-X alternative splicing and apoptosis

Claudio Sette, Pamela Bielli, Roberta Busà, Savino M. Di Stasi, Manuel J. Munoz, Flavia Botti, Alberto R. Kornblihtt

Risultato della ricerca: Contributo in rivistaArticolo in rivista

37 Citazioni (Scopus)

Abstract

Alternative splicing (AS) is tightly coupled to transcription for the majority of human genes. However, how these two processes are linked is not well understood. Here, we unveil a direct role for the transcription factor FBI-1 in the regulation of AS. FBI-1 interacts with the splicing factor SAM68 and reduces its binding to BCL-X mRNA. This, in turn, results in the selection of the proximal 5 splice site in BCL-X exon 2, thereby favoring the anti-apoptotic BCL-XL variant and counteracting SAM68-mediated apoptosis. Conversely, depletion of FBI-1, or expression of a SAM68 mutant lacking the FBI-1 binding region, restores the ability of SAM68 to induce BCL-XS splicing and apoptosis. FBI-1's role in splicing requires the activity of histone deacetylases, whose pharmacological inhibition recapitulates the effects of FBI-1 knockdown. Our study reveals an unexpected function for FBI-1 in splicing modulation with a direct impact on cell survival. Synopsis The oncogenic transcription factor FBI-1 regulates alternative splicing by preventing the splicing regulator SAM68 from binding to BCL-X mRNA. This increases anti-apoptotic BCL-X isoform expression and cell survival. The transcription factor FBI-1 directly interacts with the splicing regulator SAM68. FBI-1 impairs binding of SAM68 to BCL-X mRNA and thus promotes production of the anti-apoptotic BCL-X isoform and cell survival. FBI-1's effect on BCL-X splicing requires histone deacetylase activity. The oncogenic transcription factor FBI-1 regulates alternative splicing by preventing the splicing regulator SAM68 from binding to BCL-X mRNA. This increases anti-apoptotic BCL-X isoform expression and cell survival. © 2014 The Authors.
Lingua originaleEnglish
pagine (da-a)419-427
Numero di pagine9
RivistaEMBO Reports
Volume15
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Adaptor Proteins, Signal Transducing
  • Alternative Splicing
  • Apoptosis
  • BCL-X
  • Biochemistry
  • Cell Line, Tumor
  • DNA-Binding Proteins
  • FBI-1
  • Genetics
  • HEK293 Cells
  • Histone Deacetylase 1
  • Humans
  • Medicine (all)
  • Molecular Biology
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA, Messenger
  • RNA-Binding Proteins
  • SAM68
  • Transcription Factors
  • Two-Hybrid System Techniques
  • alternative splicing
  • apoptosis
  • bcl-X Protein

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