Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition.
Fas exon 6 can be included or skipped to generate mRNAs encoding, respectively, a membrane bound form of the receptor that promotes apoptosis or a soluble isoform that prevents programmed cell death. We report that the apoptosis-inducing protein TIA-1 promotes U1 snRNP binding to the 5' splice site of intron 6, which in turn facilitates exon definition by enhancing U2AF binding to the 3' splice site of intron 5. The polypyrimidine tract binding protein (PTB) promotes exon skipping by binding to an exonic splicing silencer and inhibiting the association of U2AF and U2 snRNP with the upstream 3' splice site, without affecting recognition of the downstream 5' splice site by U1. Remarkably, U1 snRNP-mediated recognition of the 5' splice site is required both for efficient U2AF binding and for U2AF inhibition by PTB. We propose that TIA-1 and PTB regulate Fas splicing and possibly Fas-mediated apoptosis by targeting molecular events that lead to exon definition.
Izquierdo
José María
JM
Centre de Regulació Genòmica, Passeig Marítim 37-49, 08003 Barcelona, Spain.
Majós
Nuria
N
Bonnal
Sophie
S
Martínez
Concepción
C
Castelo
Robert
R
Guigó
Roderic
R
Bilbao
Daniel
D
Valcárcel
Juan
J
D017398:Alternative Splicing; D017209:Apoptosis; D001483:Base Sequence; D005091:Exons; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D039102:Poly(A)-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins / Q000378:metabolism; D000072668:Splicing Factor U2AF; D000074019:T-Cell Intracellular Antigen-1; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism*
D009687:Nuclear Proteins; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C000607494:U2AF2 protein, human; D019014:fas Receptor; D038941:Polypyrimidine Tract-Binding Protein