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

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

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)3871-3884
TijdschriftEMBO Journal
Volume31
Nummer van het tijdschrift19
DOI's
StatusGepubliceerd - 2012

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