Study on the tumor suppressor Hippo pathway and RASSF proteins

• Project/Area Number: 26293061
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Hata Yutaka 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (80313237)
• Co-Investigator(Renkei-kenkyūsha): Iwasa Hiroaki 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (70582188) ; Maruyama Junichi 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (30723639)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: シグナル伝達 / 腫瘍抑制 / がん / 筋委縮 / 線維症 / ケミカルバイオロジー

Outline of Final Research Achievements

YAP1 and TAZ, targets of the tumor suppressor Hippo pathway, regulate cell proliferation and differentiation. Hyperactive YAP1 and TAZ provide cancer cells with malignant properties and shorten disease-free survival. On the other hands, YAP1 and TAZ play essential roles in tissue stem cells and their activities are crucial for tissue homeostasis. Thereby, YAP1 and TAZ inhibitors and activators are useful in cancer therapy and regenerative medicine, respectively. We established cell-based assays to search for YAP1 and TAZ inhibitors and activators, and performed the chemical compound screening. We characterized the obtained candidates, validated the assays and evaluated their therapeutic potentiality. We also studied RASSF6, a tumor suppressor that is closely related to the Hippo pathway. We revealed that RASSF6 blocks MDM2-mediated degradation of p53. Ras signaling strengthens the binding of RASSF6 to MDM2. In this way, RASSF6 functions as a tumor suppressor against oncogenic Ras.

Research Products

• [Journal Article] Loop diuretics affect skeletal myoblast differentiation and exercise-induced muscle hypertrophy. (2017)
  • Author(s): Mandai S, Furukawa S, Kodaka M, Hata Y, Mori T, Nomura N, Ando F, Mori Y, Takahashi D, Yoshizaki Y, Kasagi Y, Arai Y, Sasaki E, Yoshida S, Furuichi Y, Fujii NL, Sohara E, Rai T, Uchida S.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 46369-46369
  • DOI: 10.1038/srep46369
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Domain analysis of Ras-association domain family member 6 upon interaction with MDM2. (2017)
  • Author(s): Sarkar A, Iwasa H, Hossain S, Xu X, Sawada T, Shimizu T, Maruyama J, Arimoto-Matsuzaki K, Hata Y.
  • Journal Title: FEBS Letters Volume: 591 Issue: 2 Pages: 260-272
  • DOI: 10.1002/1873-3468.12551
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Hippo Pathway as Drug Targets in Cancer Therapy and Regenerative Medicine. (2017)
  • Author(s): Nagashima S, Bao Y, Hata Y.
  • Journal Title: Current Drug Targets Volume: 18 Issue: 4 Pages: 447-454
  • DOI: 10.2174/1389450117666160112115641
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury. (2016)
  • Author(s): Katano T, Fukuda M, Furue H, Yamazaki M, Abe M, Watanabe M, Nishida K, Yao I, Yamada A, Hata Y, Okumura N, Nakazawa T, Yamamoto T, Sakimura K, Takao T, Ito S.
  • Journal Title: eNeuro Volume: 3 Pages: 0110-0116
  • Peer Reviewed
• [Journal Article] Validation of the chemical compound library screening for TAZ inhibitors by use of green fluorescence protein-fused TAZ. (2016)
  • Author(s): Nagashima S, Maruyama J, Kawano S, Iwasa H, Nakagawa K, Ishigami-Yuasa M, Kagechika H, Nishina H, Hata Y.
  • Journal Title: Cancer Sci. Volume: - Issue: 6 Pages: 791-802
  • DOI: 10.1111/cas.12936
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Hippo pathway as drug targets in cancer therapy and regenerative medicine. (2016)
  • Author(s): Nagashima S, Bao Y, Hata Y.
  • Journal Title: Current Drug Targets Volume: xx
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A cell-based screening for TAZ activators identifies ethacridine, a widely used antiseptic and abortifacient, as a compound that promotes dephosphorylation of TAZ and inhibits adipogenesis in C3H10T1/2 cells. (2015)
  • Author(s): Kawano S, Maruyama J, Nagashima S, Inami K, Qiu W, Iwasa H, Nakagawa K, Ishigami-Yuasa M, Kagechika H, Nishina H, Hata Y.
  • Journal Title: J. Biochem. Volume: 158 Issue: 5 Pages: 413-423
  • DOI: 10.1093/jb/mvv051
  • NAID: 40020646985
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MAGI2/S-SCAM outside brain (2015)
  • Author(s): Nagashima S, Kodaka M, Iwasa H, Hata Y.
  • Journal Title: Journa of Biochemistry Volume: 157 Issue: 4 Pages: 177-184
  • DOI: 10.1093/jb/mvv009
  • NAID: 40020428694
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A new cell-based assay to evaluate myogenesis in mouse myoblast C2C12 cells (2015)
  • Author(s): Kodaka, M.; Yang, Z.; Nakagawa, K.; Maruyama, J.; Xu, X.; Sarkar, A.; Ichimura, A.; Nasu, Y.; Ozawa, T.; Iwasa, H.; Ishigami-Yuasa, M.; Ito, S.; Kagechika, H.; Hata, Y.
  • Journal Title: Exp. Cell. Res. Volume: 336 Issue: 2 Pages: 171-181
  • DOI: 10.1016/j.yexcr.2015.06.015
  • Peer Reviewed
• [Journal Article] Alternatively spliced isoforms of WT1 control podocyte-specific gene expression. (2015)
  • Author(s): Lefebvre J, Clarkson M, Massa F, Bradford ST, Charlet A, Buske F, Lacas-Gervais S, Schulz H, Gimpel C, Hata Y, Schaefer F, Schedl A.
  • Journal Title: Kidney International Volume: 88 Issue: 2 Pages: 321-331
  • DOI: 10.1038/ki.2015.140
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RASSF6; the Putative Tumor Suppressor of the RASSF Family. (2015)
  • Author(s): Iwasa H, Jiang X, Hata Y.
  • Journal Title: Cancers (Basel) Volume: 9 Issue: 4 Pages: 2415-2426
  • DOI: 10.3390/cancers7040899
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The mammalian Hippo pathway: regulation and function of YAP1 and TAZ. (2014)
  • Author(s): Kodaka M, Hata Y.
  • Journal Title: Cellular Molecular Life Sciences Volume: 72 Issue: 2 Pages: 285-306
  • DOI: 10.1007/s00018-014-1742-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Screening with a Novel Cell-Based Assay for TAZ Activators Identifies a Compound That Enhances Myogenesis in C2C12 Cells and Facilitates Muscle Repair in a Muscle Injury Model. (2014)
  • Author(s): Yang, Z. Y.; Nakagawa, K.; Sarkar, A.; Maruyama, J.; Iwasa, H.; Bao, Y. J.; Ishigami-Yuasa, M.; Ito, S.; Kagechika, H.; Hata, S.; Nishina, H.; Abe, S.; Kitagawa, M.; Hata, Y.
  • Journal Title: Mol. Cell. Biol. Volume: 34 Issue: 9 Pages: 1607-1621
  • DOI: 10.1128/mcb.01346-13
  • Peer Reviewed / Open Access
• [Presentation] 新規に同定したYAP1活性化化合物は多発性骨髄腫に置いてYAP1-p73経路依存的な細胞死を誘導する (2016)
  • Author(s): 丸山順一、江欣亮、岩佐宏晃、湯浅―石上磨里、影近弘之、仁科博史、畑裕
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜パシフィコ
• [Presentation] 細胞内局在を指標とする探索系による転写共役因子（TAZ）抑制剤探索の有効性の検証 (2016)
  • Author(s): 長島俊太、丸山順一、湯浅―石上磨里、影近弘之、仁科博史、畑裕
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜パシフィコ
• [Presentation] マウス筋芽C2C12細胞を用いた筋形成評価野ための新しいアセイ系の構築 (2016)
  • Author(s): 小高愛未、那須雄介、小澤岳昌、湯浅―石上磨里、伊藤茂、影近弘之、畑裕
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜パシフィコ
• [Presentation] がん治療、再生医療の治療標的としての転写共役因子YAP1、TAZの有用性について (2015)
  • Author(s): 畑裕
  • Organizer: 日本分子生物学会、日本生化学会合同大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-03
• [Presentation] UNC119Aは腫瘍抑制分子RASSF6と共にDNA損傷応答を制御する (2015)
  • Author(s): 岩佐宏晃、清水尊仁、畑裕
  • Organizer: 日本分子生物学会、日本生化学会合同大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Patent(Industrial Property Rights)] 筋形成促進剤、筋委縮抑制剤、医薬組成物及びTAZ活性化剤 (2015)
  • Inventor(s): 畑裕、影近弘之、中川健太郎、伊藤茂
  • Industrial Property Rights Holder: 畑裕、影近弘之、中川健太郎、伊藤茂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-02-06
  • Overseas