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.
Original language | English (US) |
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Pages (from-to) | 34-44 |
Number of pages | 11 |
Journal | Genes and Development |
Volume | 14 |
Issue number | 1 |
State | Published - Jan 1 2000 |
Keywords
- Angiogenesis
- Cancer
- Hypoxia
- Hypoxia-inducible factor-1 (HIF-1)
- Vascular endothelial growth factor (VEGF)
- p53
ASJC Scopus subject areas
- Genetics
- Developmental Biology