2003 Fiscal Year Final Research Report Summary
New function of NADPH-P450 reductase(NPR) : Regulation of hypoxia-response genes by NPR.
| Project/Area Number |
14572095
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Kwansei Gakuin University |
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Principal Investigator |
IMAOKA Susumu Kwansei Gakuin University, School of Science and Technology, Professor, 理工学部, 教授 (60145795)
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| Project Period (FY) |
2002 – 2003
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| Keywords | hypoxia / NADPH-P450 reductase / erythropoietin / VEGF / bisphenol A / HSP90 / HIF-1α |
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| Research Abstract |
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.
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