HIF-1α protein as a target for S-nitrosation
Hypoxia-inducible factor-1α (HIF-1α) is a master regulator to sense decreased oxygen partial pressure. HIF-1α stability regulation initiates a complex biological response that allows cells to act appropriately to meet patho-physiological situations of decreased oxygen availability. Recently, nitric...
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Veröffentlicht in: | FEBS letters 2003-01, Vol.535 (1-3), p.106-112 |
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Zusammenfassung: | Hypoxia-inducible factor-1α (HIF-1α) is a master regulator to sense decreased oxygen partial pressure. HIF-1α stability regulation initiates a complex biological response that allows cells to act appropriately to meet patho-physiological situations of decreased oxygen availability. Recently, nitric oxide emerged as a messenger with the ability to stabilize HIF-1α and to transactivate HIF-1 under normoxia. Considering that reactive nitrogen species are recognized for post-translation protein modifications, among others S-nitrosation, we asked whether HIF-1α is a target for S-nitrosation. In vitro NO+ donating NO donors such as GSNO and SNAP provoked massive S-nitrosation of purified HIF-1α. All 15 free thiol groups found in human HIF-1α are subjected to S-nitrosation. Thiol modification is not shared by spermine-NONOate, a NO radical donating compound. However, spermine-NONOate in the presence of O2−, generated by xanthine/xanthine oxidase, regained S-nitrosation, most likely via formation of a N2O3-like species. In vitro, S-nitrosation of HIF-1α was attenuated by the addition of GSH or ascorbate. In RCC4 and HEK293 cells GSNO or SNAP reproduced S-nitrosation of HIF-1α, however with a significantly reduced potency that amounted to modification of three to four thiols, only. Importantly, endogenous formation of NO in RCC4 cells via inducible NO synthase elicited S-nitrosation of HIF-1α that was sensitive to inhibition of inducible NO synthase activity with N-monomethyl-L-arginine. NO-stabilized HIF-1α was susceptible to the addition of N-acetyl-cysteine that destabilized HIF-1α in close correlation to the disappearance of S-nitrosated HIF-1α. In conclusion, HIF-1α is a target for S-nitrosation by exogenously and endogenously produced NO. |
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ISSN: | 0014-5793 1873-3468 |
DOI: | 10.1016/S0014-5793(02)03887-5 |