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The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo

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-(VEGFxxx) or anti-(VEGFxxxb) 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-VEGFxxx versus anti-VEGFxxxb 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 VEGF165b/VEGF ratio and decrease tumour neovascularization in vivo. Overall, these findings highlight E2F1 and SC35 as two regulators of the VEGFxxx/VEGFxxxb 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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Acknowledgements

We thank Patricia Betton, Pascal Perron and Celine Lampreia for technical assistance. This work was supported by the Ligue Nationale contre le Cancer (Equipe Labellisée Ligue 2007) and by the Conseil Scientifique National d’AGIR á dom. Galina Merdzhanova was supported by fellowships from the Research French Ministry and the Fondation pour la Recherche Medicale (FRM). Stephanie Gout was supported by a fellowship from Association pour la Recherche Contre le Cancer (ARC). Valerie Edmond was supported by a grant from the Conseil Scientifique National d’AGIR á dom.

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Correspondence to B Eymin.

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Merdzhanova, G., Gout, S., Keramidas, M. et al. The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo. Oncogene 29, 5392–5403 (2010). https://doi.org/10.1038/onc.2010.281

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Keywords

  • alternative splicing
  • angiogenesis
  • cancer
  • E2F1
  • SC35
  • VEGF-A

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