Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.

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-1alpha 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-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha 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.
Mesh Terms:
Adenocarcinoma, Animals, Cell Division, Colonic Neoplasms, DNA-Binding Proteins, Endothelial Growth Factors, Genotype, Humans, Hydrolysis, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Lymphokines, Mice, Neovascularization, Pathologic, Nuclear Proteins, Oxygen, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ubiquitins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
Genes Dev.
Date: Jan. 01, 2000
Download Curated Data For This Publication
5771
Switch View:
  • Interactions 2