Herr 2007 Cell Mol Life Sci
|Herr B, Zhou J, Dröse S, Brüne B (2007) The interaction of superoxide with nitric oxide destabilizes hypoxia-inducible factor-1alpha. Cell Mol Life Sci 64:3295-305.|
Abstract: In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide (NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species. A prerequisite for O2 − in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation. Using uric acid to interfere with signal transmission elicited by NO/O2 − blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O2 − coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome.
• Keywords: HIF-1α, Nitric oxide, Oxygen radicals, Calcium, Calpain, Mitochondria
• O2k-Network Lab: DE Frankfurt Droese S
Coupling state: OXPHOS