Regulation of HIF-1alpha stability through S-nitrosylation

Mol Cell. 2007 Apr 13;26(1):63-74. doi: 10.1016/j.molcel.2007.02.024.


Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional factor. Under normal oxygen tension, HIF-1 activity is usually suppressed due to the rapid, oxygen-dependent degradation of one of its two subunits, HIF-1alpha. Here we report that normoxic HIF-1 activity can be upregulated through NO-mediated S-nitrosylation and stabilization of HIF-1alpha. In murine tumors, exposure to ionizing radiation stimulated the generation of NO in tumor-associated macrophages. As a result, the HIF-1alpha protein is S-nitrosylated at Cys533 (through "biotin switch" assay) in the oxygen-dependent degradation domain, which prevents its destruction. Importantly, this mechanism appears to be independent of the prolylhydroxylase-based pathway that is involved in oxygen-dependent regulation of HIF-1alpha. Selective disruption of this S-nitrosylation significantly attenuated both radiation-induced and macrophage-induced activation of HIF-1alpha. This interaction between NO and HIF-1 sheds new light on their involvement in tumor response to treatment as well as mammalian inflammation process in general.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Cysteine / chemistry
  • Gene Expression Regulation, Neoplastic*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Macrophages / enzymology
  • Macrophages / metabolism
  • Macrophages / radiation effects
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • Neoplasms / metabolism*
  • Neoplasms / radiotherapy
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism*
  • Sequence Homology, Amino Acid
  • Transfection


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Cysteine