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. 2010 Sep 30;29(39):5392-403. doi: 10.1038/onc.2010.281. Epub 2010 Jul 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / biosynthesis*
  • Angiogenesis Inhibitors / genetics
  • Angiogenesis Inhibitors / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Serine-Arginine Splicing Factors
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inhibitors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Nuclear Proteins
  • Protein Isoforms
  • Proteins
  • RNA Precursors
  • RNA, Messenger
  • Ribonucleoproteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors