E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35.
The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the Ser-Rich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting.
Merdzhanova
G
G
INSERM, U823, Equipe 2 Bases Moléculaires de la Progression des Cancers du Poumon, Grenoble, 38042, France.
Edmond
V
V
De Seranno
S
S
Van den Broeck
A
A
Corcos
L
L
Brambilla
C
C
Brambilla
E
E
Gazzeri
S
S
Eymin
B
B
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012322:RNA Precursors / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; D012322:RNA Precursors; D012261:Ribonucleoproteins; D051020:bcl-X Protein; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D003520:Cyclophosphamide; D053181:Caspase 8; D053453:Caspase 9