2011 Fiscal Year Final Research Report
Cyclin-dependent kinase 2 down-regulates expression of drug-metabolizing enzymes UGT1A1 and CYP3A4 through phosphorylation of nuclear receptor PXR
| Project/Area Number |
21590170
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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 |
Medical pharmacy
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| Research Institution | University of Shizuoka |
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Principal Investigator |
MIWA Masao 静岡県立大学, 薬学部, 名誉教授 (10046287)
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| Co-Investigator(Kenkyū-buntansha) |
SUGATANI Junko 静岡県立大学, 薬学部, 教授 (30098131)
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| Project Period (FY) |
2009 – 2011
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| Keywords | サイクリン依存性キナーゼ / 薬物代謝酵素 / 転写調節 / 核内受容体 / シグナル伝達 / CDK2 / 細胞周期 |
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| Research Abstract |
We investigated how the expression of drug-metabolizing enzymes including UGT1A1and CYP3A4 is regulated by cell signals associated with cell-cycle progression. While the active form of CDK2(phospho-CDK2) peaked at 2 h and 4 h, respectively, and these levels dropped at 8 h, UGT1A1 and CYP2B6 were present at very low levels at 0 h to 6 h and started accumulating at 8 h. While CDK2 inhibitor roscovitine enhanced the expression of UGT1A1 and CYP3A4, it suppressed the expression of UGT1A1 and CYP3A4 in the cells transfected with S350D PXR. Phosphomimetic mutant at serine-350 of PXR was detected in the nuclei and lost the binding with RXR, and co-transfection with co-activator SRC-2 but not SRC-1 recovered PXR activity. These results indicate that roscovitine stimulated expression of UGT1A1 and CYP3A4 through inhibiting CDK2, which phosphorylated PXR at serine-350 to suppress the transactivation in the nuclei.
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