Regulation of HIF-1α Stability through S-nitrosylation
Abstract
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-1α. Here we report that normoxic HIF-1 activity can be up-regulated through NO-mediated S-nitrosylation and stabilization of HIF-1α. In murine tumors, exposure to ionizing radiation stimulated the generation of NO in tumor-associated macrophages. As a result, the HIF-1α protein is S-nitrosylated at cysteine 533 (through ‘biotin-switch’ assay) in the oxygen-dependent degradation domain, which prevents its destruction. Importantly, this mechanism appears to be independent of the prolyl hydroxylase-based pathway that is involved in oxygen-dependent regulation of HIF-1α. Selective disruption of this S-nitrosylation significantly attenuated both radiation-induced and macrophage-induced activation of HIF-1α. This interaction between NO and HIF-1 sheds new lights on their involvement in tumor response to treatment as well as mammalian inflammation process in general.
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Supplementary Data
Supplementary information includes more details of material and methods and eight additional figures.