The transcription factor E2F1 and the SR protein SC35 control the ratio between pro-versus anti-angiogenic isoforms of VEGF-A to inhibit neovascularisation in vivo

Galina Merdzhanova 1, 2 Stéphanie Gout 1, 2 Michelle Keramidas 3, 2 Valérie Edmond 1, 2 Jean-Luc Coll 3, 2 Christian Brambilla 1, 2 Elisabeth Brambilla 1, 2 Sylvie Gazzeri 1, 2 Béatrice Eymin 1, 2, *
* Corresponding author
1 Equipe 2 - Bases Moléculaires de la Progression des Cancers du Poumon, Inserm U823
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
3 Equipe 5 - Cibles Thérapeutiques et Diagnostiques et Vectorisation de Drogues dans le Cancer du Poumon
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
Abstract : 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 VEGF(xxx) mRNA levels. We further show that, strikingly, E2F1 alters the ratio of pro-VEGF(xxx) versus anti-VEGF(xxx)b angiogenic isoforms, favouring the antiangiogenic 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 VEGF(165)b/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.
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Galina Merdzhanova, Stéphanie Gout, Michelle Keramidas, Valérie Edmond, Jean-Luc Coll, et al.. The transcription factor E2F1 and the SR protein SC35 control the ratio between pro-versus anti-angiogenic isoforms of VEGF-A to inhibit neovascularisation in vivo. Oncogene, Nature Publishing Group, 2010, 29 (39), pp.5392-5403. ⟨10.1038/onc.2010.281⟩. ⟨inserm-02337625⟩

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