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2003 Fiscal Year Final Research Report Summary

The investigation for novel metabolic pathway of steroids and xenobiotics, PXR-CYP3A

Research Project

Project/Area Number 14571562
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionOKAYAMA UNIVERSITY

Principal Investigator

MASUYAMA Hisashi  Okayama University, Hospital, Instructor, 医学部・歯学部附属病院, 助手 (30314678)

Co-Investigator(Kenkyū-buntansha) HIRAMATSU Yuji  Okayama Univeristy, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (80218817)
MIZUTANI Yasushi  Okayama University, Hospital, Instructor, 医学部・歯学部附属病院, 助手 (20294465)
Project Period (FY) 2002 – 2003
Keywordspregnane X receptor / cytochrome P450 / steroidogenesis / nuclear receptor / xenobiotics / coactivator / endometrium
Research Abstract

Ligand binding, in addition to altering the conformational change of the receptor to interact with coactivators, has been shown to influence the stability of the nuclear receptors, suggesting that receptor degradation may be an important event in regulating the response duration of transactivation to the Ligand binding. And the degradation of several nuclear receptors has been demonstrated to be involved in the proteasome-mediated pathway. Previously we demonstrated that the interaction between the suppressor for gal 1 (SUG1) and vitamin D receptor was involved in proteasome-mediated degradation. In this study, we examined the potential role of SUG1 in the proteasome-mediated degradation of nuclear receptors, especially estrogen receptor (ER) and pregnane X receptor (PXR).
We checked whether or not SUG1 interacts with ER and PXR in the presence of several ligands. Next, the effects of ligands for ER and PXR on the steady states of these receptors were examined. We also examined the effe … More ct of SUG1 on ER-and PXR-mediated transcription in the presence of these ligands. Further, we used a transient transfection assay to determine whether or not the interaction of SUG1 with ER or PXR is involved in this degradation system. Finally, we checked whether or not SUG1 plays a role in the ubiquitination of ER proteins.
Both ER and PXR interacted with SUG1 in a Ligand-dependent manner. Functionally, overexpression of SUG1 inhibited both ER-and PXR-mediated transcription in the presence of ligands. Transient expression studies demonstrated that overexpression of wild-type SUG1 generated proteolytic fragments of both ER and PXR, and that these products were blocked by a proteasome inhibitor. The overexpression of SUG1 also enhanced the formation of ubiquitinated proteins of both ER and PXR in the presence of Ligand. On the other hand, some endocrine disrupting chemicals (EDC), which activated the transcription, did not enhance the interaction of SUG1 with ERb or PXR. Furthermore, the degradation of ERA or PXR was much slower in the presence of these EDCs than in the presence of endogenous ligands. Also, these EDC had no effect on the formation of proteolytic fragments of ERA, or PXR.
These findings indicate that the ubiquitin/proteasome-mediated degradation of both ER and PXR proteins may involve the interactions with SUG1 and that some EDCs may affect the nuclear receptor-mediated transcription of target genes by inhibiting the degradation of receptor proteins. Less

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] H Masuyama, H Inoshita, Y Hiramatsu, T Kudo: "Ligands have various potential effects on the degradation of pregnane X receptor by proteasome"Endocrinology. 143. 55-61 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Masuyama, J.Kodama, Y.Hirmatsu, T.Kudo: "Expression and Potential Roles of pregnane X receptor in Endometrial cancer."J Clin Endocrinol Metab. 88. 4446-4454 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Inoshita, H.Masuyama, Y.Hiramatsu: "The Different Effects of Endocrine Disrupting Chemicals on Estrogen receptor-mediated Transcription through Interaction with Coactivator TRAP220 in uterine tissue."J Mol Endocrinol. 31. 551-561 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H Masuyama, Y Hiramatsu: "Involvement of suppressor for gal-1 in the ubiquitin/ proteasome-mediated degradation of estrogen receptors."J Biol Chem. 279. 12020-12026 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 増山 寿: "プレグナンXレセプター-新しいステロイド・Xenobiotics代謝調節機構-"医学のあゆみ. 204. 964-968 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 増山 寿, 平松 祐司: "環境ホルモン作用の分子機構"産婦人科の実際. 52. 2343-2351 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Masuyama, H.Inoshita, Y.Hiramatsu, T.Kudo: "Ligands have various potential effects on the degradation of pregnane X receptor by proteasome."Endocrinol. 143. 55-61 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Ishida, Y.Hiramatsu, H.Masuyama, Y.Mizutani, T.Kudo: "Inhibition of placental ornithine decarboxylase by DL-a-difluoro-methyl ornithine causes fetal growth restriction in rat."Life Sciences. 70. 1395-1405 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Kumazawa, Y.Hiramatsu, H.Masuyama, Y.Mizutani, T.Nakata, T.Kudo: "Prediction Markers for Respiratory Distress Syndrome : Evaluation of the Stable Microbubble Test. Surfactant protein-A and Hepatocyte Growth Factor Levels in Amniotic Fluid."Acta med Okayama. 57. 25-32 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Masuyama, J.Kodama, Y.Hiramatsu, T.Kudo: "Expression and Potential Roles of Pregnane X Receptor in Endometrial Cancer."J Clin Endocrinol Metab. 88. 4446-4454 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Inoshita, H.Masuyama, Y.Hiramatsu: "The Different Effects of Endocrine Disrupting Chemicals on Estrogen receptor-mediated Transcription through Interaction with Coactivator TRAP220 in uterine tissue."J Mol Endocrinol. 31. 551-561 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H Masuyama, Y Hiramatsu: "Involvement of suppressor for gal-1 in the ubiquitin / proteasome-mediated degradation of estrogen receptors."J Biol Chem. 279. 12020-12026 (2004)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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