Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α

Denise A. Chan, Patrick D. Sutphin, Nicholas C. Denko, Amato J. Giaccia

Research output: Contribution to journalArticle

219 Scopus citations

Abstract

Stabilization of the hypoxia-inducible factor-1α (HIF-1) protein is essential for its role as a regulator of gene expression under low oxygen conditions. Here, employing a novel hydroxylation-specific antibody, we directly show that proline 564 of HIF-1α and proline 531 of HIF-2α are hydroxylated under normoxia. Importantly, HIF-1α Pro-564 and HIF-2α Pro-531 hydroxylation is diminished with the treatment of hypoxia, cobalt chloride, desferrioxamine, or dimethyloxalyglycine, regardless of the E3 ubiquitin ligase activity of the von Hippel-Lindau (VHL) tumor suppressor gene. Furthermore, in VHL-deficient cells, HIF-1α Pro-564 and HIF-2α Pro-531 had detectable amounts of hydroxylation following transition to hypoxia, indicating that the post-translational modification is not reversible. The introduction of v-Src or RasV12 oncogenes resulted in the stabilization of normoxic HIF-1α and the loss of hydroxylated Pro-564, demonstrating that oncogene-induced stabilization of HIF-1α is signaled through the inhibition of prolyl hydroxylation. Conversely, a constitutively active Akt oncogene stabilized HIF-1α under normoxia independently of prolyl hydroxylation, suggesting an alternative mechanism for HIF-1α stabilization. Thus, these results indicate distinct pathways for HIF-1α stabilization by different oncogenes. More importantly, these findings link oncogenesis with normoxic HIF-1α expression through prolyl hydroxylation.

Original languageEnglish (US)
Pages (from-to)40112-40117
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number42
DOIs
StatePublished - Oct 18 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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