Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
- Rajani Ravi1,
- Bijoyesh Mookerjee1,
- Zaver M. Bhujwalla2,
- Carrie Hayes Sutter3,
- Dmitri Artemov2,
- Qinwen Zeng1,
- Larry E. Dillehay1,
- Ashima Madan4,
- Gregg L. Semenza3,5, and
- Atul Bedi1
- 1Johns Hopkins Oncology Center, 2Department of Radiology, and 3Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287 USA; 4Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, 94305 USA
Abstract
The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1α levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1α in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.
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Footnotes
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↵5 Corresponding author.
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E-MAIL gsemenza{at}jhmi.edu; FAX (410) 955-0484.
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- Received August 2, 1999.
- Accepted November 19, 1999.
- Cold Spring Harbor Laboratory Press
