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

来自 core.kmi.open.ac.uk

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154

作者：

R Ravi，B Mookerjee，ZM Bhujwalla，CH Sutter，D Artemov，Q Zeng，LE Dillehay，A Madan，GL Semenza，A Bedi

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摘要：

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.

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关键词：

p53 hypoxia-inducible factor-1 (HIF-1 angiogenesis vascular endothelial growth factor (VEGF hypoxia cancer

DOI：

10.1101/gad.14.1.34

被引量：

3528

年份：

2000