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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)419-427
Number of pages9
JournalEMBO Reports
Volume15
Issue number4
DOIs
Publication statusPublished - 2014

Keywords

  • alternative splicing
  • apoptosis
  • BCL-X
  • FBI-1
  • SAM68

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry
  • Medicine(all)

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