Open AccessCell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF
Author(s) -
Gangjian Qin,
Raj Kishore,
Christine Dolan,
Marcy Silver,
Andrea Wecker,
Corinne Luedemann,
Tina Thorne,
Allison Hanley,
Cynthia J. Curry,
Lindsay Heyd,
Deepika Dinesh,
Marianne Kearney,
Fabio Martelli,
Toshinori Murayama,
David A. Goukassian,
Yan Zhu,
Douglas W. Losordo
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0509533103
Subject(s) - e2f1 , transcription factor , angiogenesis , regulator , biology , microbiology and biotechnology , cancer research , vascular endothelial growth factor , psychological repression , vascular endothelial growth factor a , transcriptional regulation , gene expression , vegf receptors , gene , genetics
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 endothelial 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.