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

Rajani Ravi, Bijoyesh Mookerjee, Zaver M. Bhujwalla, Carrie Hayes Sutter, Dmitri Artemov, Qinwen Zeng, Larry E. Dillehay, Ashima Madan, Gregg L. Semenza, Atul Bedi

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)34-44
Number of pages11
JournalGenes and Development
Volume14
Issue number1
StatePublished - 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

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