title: The transcription factor FBI-1 inhibits SAM68-mediated BCL-X alternative splicing and apoptosis.
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.
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors: Pamela
authors: P
authors: Bielli
authors: Roberta
authors: R
authors: Busà
authors: Savino M
authors: SM
authors: Di Stasi
authors: Manuel J
authors: MJ
authors: Munoz
authors: Flavia
authors: F
authors: Botti
authors: Alberto R
authors: AR
authors: Kornblihtt
authors: Claudio
authors: C
authors: Sette
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017398:Alternative Splicing; D017209:Apoptosis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C485514:ZBTB7A protein, human; D051020:bcl-X Protein; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1