1. Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF
- Author
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Douglas W. Losordo, Corinne Luedemann, Marcy Silver, Tina Thorne, David A. Goukassian, Deepika Dinesh, Gangjian Qin, Allison Hanley, Raj Kishore, Marianne Kearney, Fabio Martelli, Cynthia Curry, Toshinori Murayama, Yan Zhu, Lindsay Heyd, Christine Dolan, and Andrea Wecker
- Subjects
Vascular Endothelial Growth Factor A ,endocrine system ,Transcription, Genetic ,Angiogenesis ,Down-Regulation ,Biology ,medicine.disease_cause ,chemistry.chemical_compound ,Mice ,medicine ,Transcriptional regulation ,E2F1 ,Animals ,Humans ,E2F ,Cells, Cultured ,Mice, Knockout ,Multidisciplinary ,Cell growth ,Cell Cycle ,Cell cycle ,Biological Sciences ,Cell biology ,Hindlimb ,Vascular endothelial growth factor ,Mice, Inbred C57BL ,chemistry ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Tumor Suppressor Protein p53 ,Carcinogenesis ,E2F1 Transcription Factor - 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 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.
- Published
- 2006