E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1
- Authors
- Weijts, B.G., Bakker, W.J., Cornelissen, P.W., Liang, K.H., Schaftenaar, F.H., Westendorp, B., de Wolf, C.A., Paciejewska, M., Scheele, C.L., Kent, L., Leone, G., Schulte-Merker, S., and de Bruin, A.
- ID
- ZDB-PUB-120822-27
- Date
- 2012
- Source
- The EMBO journal 31(19): 3871-3884 (Journal)
- Registered Authors
- Schulte-Merker, Stefan
- Keywords
- angiogenesis, E2F, HIF, VEGF, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Line, Tumor
- E2F Transcription Factors/genetics
- E2F Transcription Factors/metabolism*
- Embryonic Development/genetics
- Embryonic Development/physiology
- Gene Deletion
- Humans
- Hypoxia-Inducible Factor 1/metabolism*
- Mice
- Neovascularization, Physiologic/genetics*
- Promoter Regions, Genetic
- Transcriptional Activation*
- Vascular Endothelial Growth Factor A/genetics*
- Zebrafish
- PubMed
- 22903062 Full text @ EMBO J.
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.