E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1

B.G.M.W. Weijts, W.J. Bakker, P.W.A. Cornelissen, K. Liang, F.H. Schaftenaar, B. Westendorp, C.A.C.M.T. de Wolf, M. Paciejewska, C.L.G.J. Scheele, L. Kent, G. Leone, S. Schulte-Merker, A. de Bruin

Research output: Contribution to journalArticleAcademicpeer-review

68 Citations (Scopus)

Abstract

The E2F family of transcription factors plays an important role in controlling cell-cycle progression. While this is their best-known function, we report here novel functions for the newest members of the E2F family, E2F7 and E2F8 (E2F7/8). We show that simultaneous deletion of E2F7/8 in zebrafish and mice leads to severe vascular defects during embryonic development. Using a panel of transgenic zebrafish with fluorescent-labelled blood vessels, we demonstrate that E2F7/8 are essential for proper formation of blood vessels. Despite their classification as transcriptional repressors, we provide evidence for a molecular mechanism through which E2F7/8 activate the transcription of the vascular endothelial growth factor A (VEGFA), a key factor in guiding angiogenesis. We show that E2F7/8 directly bind and stimulate the VEGFA promoter independent of canonical E2F binding elements. Instead, E2F7/8 form a transcriptional complex with the hypoxia inducible factor 1 (HIF1) to stimulate VEGFA promoter activity. These results uncover an unexpected link between E2F7/8 and the HIF1-VEGFA pathway providing a molecular mechanism by which E2F7/8 control angiogenesis.
Original languageEnglish
Pages (from-to)3871-3884
JournalThe EMBO Journal
Volume31
Issue number19
DOIs
Publication statusPublished - 2012

Keywords

  • hypoxia-inducible factor-1
  • growth-factor gene
  • embryonic-development
  • vascular development
  • o-2 homeostasis
  • factor 1-alpha
  • zebrafish
  • proliferation
  • cancer
  • hif-1-alpha

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