Abstract
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.
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Abbreviations
- CAT:
-
chloramphenicol acetyl transferase
- ChIP:
-
chromatin immunoprecipitation
- Fas L:
-
Fas ligand
- FLIP:
-
FLICE inhibitory protein
- MEF:
-
murine embryonic fibroblast
- p54nrb:
-
p54 nuclear RNA-binding protein
- PSF:
-
polypyrimidine tract-binding protein-associated splicing factor
- RRM:
-
RNA recognition motif
- siRNA:
-
small interfering RNA
- SR:
-
ser-rich
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
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Acknowledgements
We thank Patricia Betton, Pascal Perron and Celine Lampreia for technical assistance. We thank Johann Soret (IGM, Montpellier) for the pECE-SC35HA and Alain Sureau (CGM, Gif sur Yvette) for pR264-CAT plasmids. We thank Didier Auboeuf, Martin Dutertre, Saadi Khochbin, Johann Soret and Jamal Tazi for encouraging discussions and critical reading of this paper. We thank Mary Callanan (INSERM U823) for help with editing. This work was supported by grants from the region Rhône Alpes (Thématique Prioritaire Cancer and Canceropole 2003: Oncocell, Epimed and INACancer), by the Ligue contre le Cancer (Comité de Savoie), by the Ligue Nationale contre le Cancer (Equipe Labellisée), by INCa (PNES, Programme National d'Excellence Spécialisé 2005) and by the Conseil Scientifique National d'AGIR à dom. Arnaud van den Broeck was supported by a fellowship from the French Research Ministry. Galina Merdzhanova was supported by fellowships from the French Research Ministry and the Fondation pour la Recherche Medicale (FRM). Valerie Edmond was supported by a grant from the Conseil Scientifique National d'AGIR à dom. Sandrine De Seranno was supported by a grant from INCa.
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Merdzhanova, G., Edmond, V., De Seranno, S. et al. E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35. Cell Death Differ 15, 1815–1823 (2008). https://doi.org/10.1038/cdd.2008.135
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DOI: https://doi.org/10.1038/cdd.2008.135
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