期刊
ONCOGENE
卷 29, 期 39, 页码 5392-5403出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.281
关键词
alternative splicing; angiogenesis; cancer; E2F1; SC35; VEGF-A
资金
- Ligue Nationale contre le Cancer
- Conseil Scientifique National d'AGIR a dom
- Research French Ministry
- Fondation pour la Recherche Medicale (FRM)
- Association pour la Recherche Contre le Cancer (ARC)
- Conseil Scientifique National d'AGIR
The transcription factor E2F1 has a crucial role in the control of cell growth and has been shown to regulate neoangiogenesis in a p53-dependent manner through inhibition of activity of the VEGF-A (vascular endothelial growth factor) promoter. Besides being regulated by transcription, VEGF-A is also highly regulated by pre-mRNA alternative splicing, resulting in the expression of several VEGF isoforms with either pro-(VEGF(xxx)) or anti-(VEGF(xxx)b) angiogenic properties. Recently, we identified the SR (Ser-Rich/Arg) protein SC35, a splicing factor, as a new transcriptional target of E2F1. Here, we show that E2F1 downregulates the activity of the VEGF-A promoter in tumour cells independently of p53, leading to a strong decrease in VEGFxxx mRNA levels. We further show that, strikingly, E2F1 alters the ratio of pro-VEGF(xxx) versus anti-VEGF(xxx)b angiogenic isoforms, favouring the anti-angiogenic isoforms, by a mechanism involving the induction of SC35 expression. Finally, using lung tumour xenografts in nude mice, we provide evidence that E2F1 and SC35 proteins increase the VEGF165b/VEGF ratio and decrease tumour neovascularization in vivo. Overall, these findings highlight E2F1 and SC35 as two regulators of the VEGF(xxx)/VEGF(xxx)b angiogenic switch in human cancer cells, a role that could be crucial during tumour progression, as well as in tumour response to antiangiogenic therapies. Oncogene (2010) 29, 5392-5403; doi: 10.1038/onc. 2010.281; published online 19 July 2010
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