Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF

Gangjian Qin*, Raj Kishore, Christine M. Dolan, Marcy Silver, Andrea Wecker, Corinne N. Luedemann, Tina Thorne, Allison Hanley, Cynthia Curry, Lindsay Heyd, Deepika Dinesh, Marianne Kearney, Fabio Martelli, Toshinori Murayama, David A. Goukassian, Yan Zhu, Douglas W. Losordo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

The transcription factor E2F1 is known to regulate cell proliferation and has been thought to modulate tumorigenesis via this mechanism alone. Here we show that mice deficient in E2F1 exhibit enhanced angiogenesis. The proangiogenic phenotype in E2F1 deficiency is the result of overproduction of vascular endothetial growth factor (VEGF) and is prevented by VEGF blockade. Under hypoxic conditions, E2F1 down-regulates the expression of VEGF promoter activity by associating with p53 and specifically down-regulating expression of VEGF but not other hypoxia-inducible genes, suggesting a promoter structure context-dependent regulation mechanism. We found that the minimum VEGF promoter mediating transcriptional repression by E2F1 features an E2F1-binding site with four Sp-1 sites in close proximity. These data disclose an unexpected function of endogenous E2F1: regulation of angiogenic activity via p53-dependent transcriptional control of VEGF expression.

Original languageEnglish (US)
Pages (from-to)11015-11020
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number29
DOIs
StatePublished - Jul 18 2006

Keywords

  • E2F
  • Endothelial cell

ASJC Scopus subject areas

  • General

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