Regulation of HIF-1alpha stability through S-nitrosylation.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Li, F; Sonveaux, P; Rabbani, ZN; Liu, S; Yan, B; Huang, Q; Vujaskovic, Z; Dewhirst, MW; Li, C-Y

Published Date

  • April 13, 2007

Published In

Volume / Issue

  • 26 / 1

Start / End Page

  • 63 - 74

PubMed ID

  • 17434127

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2007.02.024

Language

  • eng

Conference Location

  • United States