Identification of novel functions of the p14ARF tumor suppressor protein

Research Project

Project/Area Number	16K08222
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Biological pharmacy
Research Institution	Hokkaido University
Principal Investigator	Nakagawa Koji 北海道大学, 薬学研究院, 講師 (80360949)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000) Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) 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	p14ARF / SIRT1 / Nrf2 / PIAS1 / 細胞老化 / がん抑制遺伝子 / 脱アセチル化 / シグナル伝達 / 癌抑制遺伝子 / 発がん抑制
Outline of Final Research Achievements	In this project, we studied novel functions of the p14ARF tumor suppressor protein. It was revealed that p14ARF physically interacts with SIRT1 deacetylase that exhibits anti-senescence activity and inhibits its deacetylase activity. In addition, we found that p14ARF negatively regulates gene transcription mediated by transcription factors FOXO3a and HIF-1, both of which are substrates of deacetylation by SIRT1. Furthermore, it was also found that p14ARF stabilizes complex formation between the oxidative stress-responsive transcription factor Nrf2 and the transcriptional cofactor PIAS1 and potentiates Nrf2-mediated gene expression.
Academic Significance and Societal Importance of the Research Achievements	本研究の結果から、がん抑制遺伝子産物であるp14ARFは、脱アセチル酵素SIRT1および酸化ストレス応答性転写因子Nrf2の活性制御因子として機能することが明らかとなった。SIRT1およびNrf2は、いずれも細胞のがん化に関与することから、今回得られた新規の知見は、p14ARFを介した発がん抑制機構を理解する上で重要であると考えられえる。本研究の成果を基として、p14ARFによる発がん抑制の分子機構の解明がさらに進めば、p14ARF経路を標的とした新規のがん治療法や抗がん剤開の開発につながることが期待できる。