期刊
MOLECULAR CELL
卷 26, 期 1, 页码 63-74出版社
CELL PRESS
DOI: 10.1016/j.molcel.2007.02.024
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资金
- NCI NIH HHS [CA81512, CA40355, R01 CA081512-09, R01 CA081512] Funding Source: Medline
- NIBIB NIH HHS [R21 EB001882] Funding Source: Medline
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-1 alpha. Here we report that normoxic HIF-1 activity can be upregulated through NO-mediated S-nitrosylation and stabilization of HIF-1 alpha. In murine tumors, exposure to ionizing radiation stimulated the generation of NO in tumor-associated macrophages. As a result, the HIF-1 alpha 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-1 alpha. Selective disruption of this S-nitrosylation significantly attenuated both radiation-induced and macrophage-induced activation of HIF-1 alpha. 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.
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