New function of NADPH-P450 reductase(NPR) : Regulation of hypoxia-response genes by NPR.

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Hypoxia is a common feature of many cancers. It contributes local and systemic tumor progression. Hypoxia is also an important factor in myocardial infarction. In hypoxic condition, hypoxia-inducible factor(HIF-1α) is stabilized and transcriptionally regulates hypoxia-response genes such as erythropoietin(EPO) and VEGF, by recognition of hypoxia response element(HRE). We found that NADPH-P450 reductase(NPR) was necessary for stabilization of HIF-1α. When NPR expression in Hep3B cells was suppressed by knockdown, HIF-1α protein was degraded. We also found that bisphenol A(BpA), an endocrine-disrupting chemical, degraded HIF-1α under hypoxia. BpA didn't interact with NPR but did with a chaperon protein, HSP90. HSP90 stabilized HEF-1α under hypoxia and BpA dissociated HSP-90 from HIF-1α. HIF-1α is known to be degraded by ubiquitination and proteasome pathway BpA degraded HIF-1α even in the presence of inhibitors for ubiquitination and proteasome degradation. These results suggested that BpA degraded HIF-1α via a currently unknown pathway. Furthermore, we searched factors which interact with NPR using yeast two-hybrid system. Some candidates were obtained and seem to contribute to the redox regulation of the cells. Further analysis for biological functions of these factors is necessary.