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

Research Project

Project/Area Number 14572095
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionKwansei Gakuin University

Principal Investigator

IMAOKA Susumu  Kwansei Gakuin University, School of Science and Technology, Professor, 理工学部, 教授 (60145795)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordshypoxia / NADPH-P450 reductase / erythropoietin / VEGF / bisphenol A / HSP90 / HIF-1α / 低酸素 / 活性酸素
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.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] M.Osada, S.Imaoka, T.Sugimoto et al.: "NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1."Journal of Biological Chemistry. 277(26). 23367-23373 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] A.Kinoshita, H.Wanibuchi, S.Imaoka et al.: "Formation of 8-hydroxydeoxyguanosine and cell-cycle arrest in the rat liver via generation of oxidative stress by phenobarbital"Carcinogenesis. 23(2). 341-349 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] A.Kinoshita, H.Wanibuchi, K.Morimura et al.: "Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression."Carcinogenesis. 24(8). 1389-1399 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Imaoka, M.Osada, Y.Minamiyama et al.: "Role of phenobarbital-inducible cytochrome P45Os as a source of active oxygen species in DNA-oxidation."Cancer Letters. 203(2). 117-125 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Kubo, N.Maezawa, M.Osada et al.: "Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1 (HIF-1alpha)"Biochemical and Biophysical Research Communications. 318(4). 1006-1011 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] M.Osada, S.Imaoka, T.Sugimoto, T.Hiroi, Y.Funae: "NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1."J.Biol.Chem.. 277(26). 23367-23373 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] A.Kinoshita, H.Wanibuchi, S.Imaoka, M.Ogawa, C.Masuda, K.Morimura, Y.Funae, S.Fukushima: "Formation of 8-hydroxydeoxy-guanosine and cell-cycle arrest in the rat liver via generation of oxidative stress by phenobarbital : association with expression profiles of p21(WAF1/Cip1), cyclin D1 and Ogg1."Carcinogenesis. 23(2). 341-349 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] A.Kinoshita, H.Wanibuchi, K.Morimura, M.Wei, J.Shen, S.Imaoka, Y.Funae, S.Fukushima: "Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression."Carcinogenesis. 24(8). 1389-1399 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Imaoka, M.Osada, Y.Minamiyama, T.Yukimura, S.Toyokuni, S.Takemura, T.Hiroi, Y.Funae: "Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation."Cancer Lett.. 203(2). 117-125 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Kubo, N.Maezawa, M.Osada, S.Katsumura, Y.Funae, S.Imaoka: "Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1(HIF-1alpha) ; Structural requirement of bisphenol A for degradation of HIF-1alpha."Biopchem.Biophys.Res.Gommun.. 318(4). 1006-1011 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kinoshita, A., Wanibuchi, H., Morimura, K., Wei, M., Shen, J., Imaoka, S., et al.: "Phenobarbital at low dose exerts hormesis in rat heapatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression."Carcinogenesis. 24(8). 1389-1399 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuno, D., Takahashi, Y., Hiroi, T., Imaoka, S., Kamataki, T., Funae, Y.: "A novel transcriptional element which regulates expression of the CYP2D4 gene by Oct-1 and YY-1 binding."Biochim.Biophys.Acta. 1627(2-3). 121-128 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuno, D., Hiroi, T., Ng, P., Kishimoto, W., Imaoka, S., Funae, Y.: "Regulation of CYP2D expression in rat brain by toluene."Osaka City Med.J.. 49(1). 49-56 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ayajiki, K., Fujioka, H., Toda, N., Okada, S., Minamiyama, Y., Imaoka, S., et al.: "Mediation of arachidonic acid metabolite(s) produced by endothelial cytochrome P-450 3A4 in monkey arterial relaxation."Hypertens.Res.. 26(3). 237-243 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Imaoka S., Osada M., Minamiyama Y., Yukimura T., Toyokuni S., et al.: "Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation."Cancer Lett.. 203(2). 117-125 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kishimoto, W., Hiroi, T., Shiraishi, M., Osada, M., Imaoka, S., Kominami, S., et al.: "Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain"Endocrinology. 145(2). 699-705 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Osada M., Imaoka S., Sugimoto T., Hiroi T., Funae Y.: "NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1"J. Biol. Chem.. 277(26). 23367-23373 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroi T., Chow T., Imaoka S., Funae Y.: "Catalytic specificity of CYP2D isoforms in rat and human"Drug Metab. Dispos.. 30(9). 970-976 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamaguchi Y., Kirita S., Hasegawa H., Aoyama J., Imaoka S.et al.: "Contribution of CYP4A8 to the formation of 20-hydroxyeicosatetraenoic acid from arachidonic acid in rat kidney"Drug Metabol. Pharmacokin.. 17(2). 109-116 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kamada T., Chow T., Hiroi T., Imaoka S., Morimoto K.et al.: "Metabolism of seleginine hydrochloride, a selective monoamine B-type inhibitor, in human liver microsomes"Drug Metabol. Pharmacokin.. 17(3). 199-206 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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