Regulatory mechanisms of MAPK signaling and its application to chemicalgenomics

研究成果の概要（和文): 本研究は, 遺伝学的と薬理学を融合した独自のケミカルゲノミクスを展開し, その成果として, 細胞増殖とがん化の鍵を握るマップキナーゼ（MAPK）シグナルの調節機構を明らかにし, MAPKシグナルを標的とした創薬を展開した. 具体的には, MAPKの活性化に関わる遺伝子群や標的遺伝子の同定に加え、MAPKシグナルを制御できる化合物を発見した. さらに, 免疫抑制薬であるFK506, RapamycinやFTY720の感受性を決定する遺伝子群を同定し, これらの遺伝子とMAPK経路のクロストーク機構を明らかにした. これらの成果は, MAPKシグナルの破綻が引き起こすがんを始めとした疾患治療法開発に貢献する. 研究成果の概要（英文): The purpose of this research project was to elucidate novel regulatory mechanisms of the Pmk1 MAPK signaling pathway in fission yeast and its application to genome-based drug discovery. We performed chemicalgenomics screens, utilizing the functional interaction between MAPK and calcineurin, and identified regulators (such as Cwg2, Rho4 and Rho5) and targets of Pmk1 MAPK in addition to several compounds that modify the ERK MAPK signaling pathway in mammals. Furthermore, we performed genome-wide identification of the genes involved in the sensitivities to FK506, Rapamycin and FTY720 and elucidated as-yet-unidentified functional interactions between MAPK and these gene products. Collectively, our data will contribute to the development of novel and effective therapeutic approaches for diseases associated with abrogated MAPK signaling activity.研究種目：基盤研究(B); 研究期間：2011～2014; 課題番号：23390021; 研究分野：分子遺伝学, 細胞生物学, ゲノム薬理学, 分子細胞生物学, シグナル伝達, ゲノム創薬; 科研費の分科・細目