Role of YAP1/TAZ in cell competition

• Project/Area Number: 16K08626
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kobe University
• Principal Investigator: Nishio Miki 神戸大学, 医学研究科, 講師 (10467897)
• Research Collaborator: MIYACHI Yosuke ; OTANI Junji ; TANE Shoji ; OMORI Hirofumi ; UEDA Fumihito ; MAEHAMA Tomohiko ; SUZUKI Akira
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: YAP1 / 細胞競合 / 細胞間コミュニケーション / Hippo経路 / 接着分子 / Hippo

Outline of Final Research Achievements

In mammalian cells, the cell with constitutively active YAP became "loser" and eliminated by the cell competition. This type of cell competition was observed in NIH3T3 cell and PAM cell in addition to previously reported MDCK cell. YAP-activated cells were prone to extrude and form a multi-stacked cell layer, when cultured with wild-type cells that were tightly attached to culture vessels and grew within flat monolayer. In contrast, when cultured on low-binding culture vessels, the YAP-activated cells turned to be "winner", because YAP-activated cells retained proliferation ability in anchorage-independent manner but wild-type cells did not. Intriguingly, in both cases, ECM coating of culture vessels strengthened binding of "loser" cells to the vessels and restored their proliferation, blunting "loser" cell elimination by cell competition. These observations suggest that the binding of cells to culture vessels and ECM may play a role in cell competition of mammalian cells.

Academic Significance and Societal Importance of the Research Achievements

異なる形質を有する同種の細胞間で適応度の高い細胞が生き残り、適応度の低い細胞が排除される「競合」現象が生じることが哺乳類細胞においても報告されたが、この細胞間コミュニケーション制御機構に関与する遺伝子群はほとんど分かっていなかった。本研究ではこの細胞間「競合」現象におけるYAP1の役割を詳細に解析することで、哺乳類細胞の細胞間コミュニケーション制御機構におけるHippo経路の関与を明らかにした。

Research Products

• [Journal Article] Hippo pathway controls cell adhesion and context-dependent cell competition to influence skin engraftment efficiency (2019)
  • Author(s): Nishio Miki、Miyachi Yousuke、Otani Junji、Tane Shoji、Omori Hirofumi、Ueda Fumihito、Togashi Hideru、Sasaki Takehiko、Mak Tak Wah、Nakao Kazuwa、Fujita Yasuyuki、Nishina Hiroshi、Maehama Tomohiko、Suzuki Akira
  • Journal Title: The FASEB Journal Volume: 33 Issue: 4 Pages: 5548-5560
  • DOI: 10.1096/fj.201802005r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/TAZ-TEAD-dependent repression of SOX9. (2018)
  • Author(s): Goto H, Nishio M, To Y, Oishi T, Miyachi Y, Maehama T, Nishina H, Akiyama H, Mak TW, Makii Y, Saito T, Yasoda A, Tsumaki N, Suzuki A.
  • Journal Title: Development Volume: 145 Issue: 6 Pages: 159244-159244
  • DOI: 10.1242/dev.159244
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. (2017)
  • Author(s): Nambara S, Masuda T, Nishio M, Kuramitsu S, Tobo T, Ogawa Y, Hu Q, Iguchi T, Kuroda Y, Ito S, Eguchi H, Sugimachi K, Saeki H, Oki E, Maehara Y, Suzuki A, Mimori K
  • Journal Title: Oncotarget. Volume: 8(64) Issue: 64 Pages: 107666-107677
  • DOI: 10.18632/oncotarget.22587
  • NAID: 120006454566
  • Peer Reviewed / Open Access
• [Journal Article] YAP determines the cell fate of injured mouse hepatocytes in vivo (2017)
  • Author(s): Miyamura N, Hata S, Itoh T, Tanaka M, Nishio M, Itoh M, Ogawa Y, Terai S, Sakaida I, Suzuki A, Miyajima A, Nishina H.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 16017-16017
  • DOI: 10.1038/ncomms16017
  • NAID: 120006373756
  • Peer Reviewed / Open Access
• [Journal Article] Hippo vs. Crab: tissue-specific functions of the mammalian Hippo pathway (2017)
  • Author(s): M. Nishio, T. Maehama, H. Goto, K. Nakatani, W. Kato, H. Omori, Y. Miyachi, H. Togashi, Y. Shimono and A. Suzuki
  • Journal Title: Genes to Cells Volume: 22 Issue: 1 Pages: 6-31
  • DOI: 10.1111/gtc.12461
  • Peer Reviewed / Open Access
• [Journal Article] Altered expression of Hippo signaling pathway molecules in intrahepatic cholangiocarcinoma. (2017)
  • Author(s): Sugimachi K, Nishio M, Aishima S, Kuroda Y, Iguchi T, Komatsu H, Hirata H, Sakimura S, Eguchi H, Bekki Y, Takenaka K, Maehara Y, Suzuki A, Mimori K.
  • Journal Title: ONCOLOGY Volume: - Issue: 1 Pages: 67-74
  • DOI: 10.1159/000463390
  • Peer Reviewed / Open Access
• [Journal Article] MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. Oncogene (2017)
  • Author(s): Otsubo K, Goto H, Nishio M, Kawamura K, Yanagi S, Nishie W, Sasaki T, Maehama T, Nishina H, Mimori K, Nakano T, Shimizu H, Mak TW, Nakao K, Nakanishi Y, Suzuki A
  • Journal Title: Oncogene Volume: 印刷中 Issue: 29 Pages: 4201-4211
  • DOI: 10.1038/onc.2017.58
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice. (2016)
  • Author(s): Matsushita Y, Sakai Y, Shimmura M, Shigeto H, Nishio M, Akamine S, Sanefuji M, Ishizaki Y, Torisu H, Nakabeppu Y, Suzuki A, Takada H, Hara T.
  • Journal Title: Sci Rep Volume: 未 Issue: 1 Pages: 22991-22991
  • DOI: 10.1038/srep22991
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Hippo経路とその破綻病態 (2018)
  • Author(s): 西尾美希、大森裕文、藤 庸子、中谷圭佑、青野ゆかり、清野 透、益田宗幸、中川尚志、片渕秀隆、田代浩徳、前濱朝彦、鈴木 聡
  • Organizer: 第41回日本分子生物学会年会（MBSJ2018）
  • Invited
• [Presentation] Hippo経路分子Mob1変異による肝がん発症機構 (2017)
  • Author(s): 西尾美希、杉町圭史、新家一男、三森功士、鈴木 聡
  • Organizer: 第54回 日本臨床分子医学会学術集会
• [Presentation] Hippo signaling pathway affects cell competion in mammalian cells via cell-ECM binding and anchorage-dependent cell proliferation (2017)
  • Author(s): Miki Nishio, Tomohiko Maehama, Akira Suzuki
  • Organizer: 3rd International Symposium on Cell Competition
• [Presentation] Hippoシグナル経路による細胞増殖変化と細胞間コミュニケーション (2017)
  • Author(s): 西尾美希、前濱朝彦、上田史仁、鈴木聡
  • Organizer: 新学術領域「幹細胞老化と疾患」「細胞競合」総括班主催「若手の会」
• [Presentation] Role of Hippo pathway in vivo (2016)
  • Author(s): Miki Nishio, Hiroki Goto, Kohei Otsubo, Hideru Togashi, Yohei Shimono, Tomohiko Maehama, Akira Suzuki
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] The Hippo signaling Pathway: Function, Disorders, and Therapeutic Targeting (2016)
  • Author(s): Miki Nishio, Hiroki Goto, Yousuke Miyachi, Hideru Togashi, Yohei Shimono, Akira Suzuki
  • Organizer: The 89th Annual Meeting of the Japanese Biochemical Society
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] 遺伝子改変動物を利用した,形態形成におけるHippo経路の機能解析 (2016)
  • Author(s): 田中雅人, 後藤裕樹, 西尾美希, 中谷圭佑, 前濱朝彦, 富樫 英, 下野洋平, 鈴木 聡
  • Organizer: 第48回日本臨床分子形態学会
  • Place of Presentation: 熊本
  • Year and Date: 2016-09-23
  • Invited