Role and mechanism of PP2A phosphorylation in mutagenic pathway

• Project/Area Number: 16K18927
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Environmental and hygienic pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Ishii Yuji 国立医薬品食品衛生研究所, 病理部, 室長 (70544881)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PP2A / 変異原性 / gpt delta / フェニルプロぺノイド化合物 / 薬学 / 遺伝毒性 / 遺伝子突然変異

Outline of Final Research Achievements

PP2A phosphorylation at Tyr307 and hepatocyte proliferation were observed in the liver of rats treated with allylalkoxy benzene compounds, eugenol, methyleugenol and estragole, regardless of mutagenicity. In addition, DNA microarray analysis revealed that expression of cell proliferation-related genes, Mybl2 and E2f8, was commonly upregulated in those treated rats. Therefore, hepatocyte proliferation might be attributed to allylalkoxy bezene structure. On the other hand, the effects of PP2A inhibitor on mutagenicity in the livers of gpt delta rats treated with estragole were not clearly demonstrated under current experimental condition.

Academic Significance and Societal Importance of the Research Achievements

アリルアルコキシベンゼンは食品等を介してヒトが非意図的に暴露される可能性のある物質であり、その健康影響が懸念されている。本研究で明らかになったPP2Aリン酸化と細胞増殖がエストラ―ル、メチルオイゲノー、オイゲノールの3剤に共通して見られた事実は、これらの変化がこれらの共通骨格に由来する可能性を示すものであり、他のアリルアルコキシベンゼン類の安全性を考えるうえでも有用な知見である。