Chemical compound screening and development for Hippo signaling pathway

• Project/Area Number: 23790325
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAKAGAWA KENTARO 東京医科歯科大学, 医歯(薬)学総合研究科, 講師 (70451929)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 化合物ライブラリー / 創薬 / 筋萎縮 / Hippo pathway / 転写コアクチベーター / 低分子化合物 / Hippoシグナル伝達系 / 薬剤探索 / 腫瘍抑制 / 骨格筋再生 / ハイコンテントスクリーニング / 腫瘍抑制因子 / リン酸化

Research Abstract

The mammalian Hippo pathway is composed of mammalian Ste20-like (MST) kinases and large tumor suppressor (LATS) kinases. Upon the activation of the pathway, transcriptional co-activator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are phosphorylated and recruited to the cytosol from the nucleus, and gene transcription is turned off. TAZ cooperates with various transcriptional factors and plays various roles. We developed a cell-based assay using sphere formation by TAZ-expressing MCF10A cells as a readout to screen 18,458 chemical compounds for TAZ activators. In this study, we focused on one compound, IBS008738. IBS008738 facilitates muscle repair in cardiotoxin-induced muscle injury and prevents dexamethasone-induced muscle atrophy. Thus, this cell-based assay is useful to identify TAZ activators with a variety of cellular outputs. Our findings also support the idea that TAZ is a potential therapeutic target for muscle atrophy.

Research Products

• [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, Nakagawa K, Sarkar A, Maruyama J, Iwasa H, Bao Y, Ishigami-Yuasa M, Ito S, Kagechika H, Hata S, Nishina H, Abe S, Kitagawa M, Hata Y
  • Journal Title: Mol. Cell Biol Volume: 34巻9号 Pages: 1607-1621
  • Peer Reviewed
• [Journal Article] RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer (2014)
  • Author(s): Fukatsu A, Ishiguro F, Tanaka I, Kudo T, Nakagawa K, Shinjo K, Kondo Y, Fujii M, Hasegawa Y, Tomizawa K, Mitsudomi T, Osada H, Hata Y, Sekido Y
  • Journal Title: Lung Cancer Volume: 83巻1号 Pages: 23-296
  • Peer Reviewed
• [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
• [Journal Article] The RASSF6 tumor suppressor protein regulates apoptosis an the cell cycle via MDM2 protein and p53 protein (2013)
  • Author(s): Iwasa H, Kudo T, Maimaiti S, Ikeda M, Maruyama J, Nakagawa K, Hata Y
  • Journal Title: J. Biol. Chem Volume: 288巻42号 Pages: 30320-30329
  • Peer Reviewed
• [Journal Article] Yes-associated protein homolog, YAP-1, is involved in the thermotolerance and aging in the nematode Caenorhabditis elegans (2013)
  • Author(s): Iwasa H, Maimaiti S, Kuroyanagi H, Kawano S, Inami K, Timalsina S, Ikeda M, Nakagawa K, Hata Y
  • Journal Title: Exp. Cell Res Volume: 319巻7号 Pages: 931-945
  • Peer Reviewed
• [Journal Article] Characterization of RSF-1, the Caenorhabditis elegans homolog of the Ras-association domain family protein 1 (2013)
  • Author(s): Iwasa H, Kuroyanagi H, Maimaiti S, Ikeda M, Nakagawa K, Hata Y
  • Journal Title: Exp. Cell Res Volume: 319巻3号 Pages: 1-11
  • Peer Reviewed
• [Journal Article] The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle via MDM2 protein and p53 protein. (2013)
  • Author(s): Iwasa H, Kudo T, Maimaiti S, Ikeda M, Maruyama J, Nakagawa K, Hata Y.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 42 Pages: 30320-9
  • DOI: 10.1074/jbc.m113.507384
  • Peer Reviewed
• [Journal Article] RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer. (2013)
  • Author(s): Fukatsu A, Ishiguro F, et al.
  • Journal Title: Lung Cancer Volume: 83 Issue: 1 Pages: 23-29
  • DOI: 10.1016/j.lungcan.2013.10.014
  • Peer Reviewed
• [Journal Article] Characterization of RSF-1, the Caenorhabditis elegans homolog of the Ras-association domain family protein 1 (2013)
  • Author(s): Iwasa H, Kuroyanagi H, Maimaiti S, Ikeda M, Nakagawa K, Hata Y
  • Journal Title: Experimental Cell Research Volume: 319 Issue: 3 Pages: 1-11
  • DOI: 10.1016/j.yexcr.2012.10.008
  • Peer Reviewed
• [Journal Article] Yes-associated protein homolog, YAP-1, is involved in the thermotolerance and aging in the nematode Caenorhabditis elegans (2013)
  • Author(s): Iwasa H, Maimaiti S, Kuroyanagi H, Kawano S, Inami T, Ikeda M, Nakagawa K, Hata Y
  • Journal Title: Experimental Cell Research Volume: 319 Issue: 7 Pages: 931-945
  • DOI: 10.1016/j.yexcr.2013.01.020
  • Peer Reviewed
• [Journal Article] Cancer susceptibility and embryonic lethality in Mob1A/1B double mutant mice (2012)
  • Author(s): Nishio M, Hamada K, Kawahara K, Sasaki M, Noguchi F, Chiba S, Mizuno K, Suzuki S, Dong Y, Tokuda M, Morikawa T, Hikasa H, Eggenschwiler J, Yabuta N, Nojima H, Nakagawa K, Hata Y, Nishina H, Mimori K, Mori M, Sasaki T, Mak TW, Nakano T, Itami S, Suzuki A
  • Journal Title: J. Clin. Invest Volume: 122巻12号 Pages: 4505-4518
  • Peer Reviewed
• [Journal Article] The RASSF3 candidate tumor suppressor induces apoptosis and G1/S cell cycle arrest via p53 (2012)
  • Author(s): Kudo T, Ikeda M, Nishikawa M, Yang Z, Ohno K, Nakagawa K, Hata Y
  • Journal Title: Cancer Res Volume: 72巻11号 Pages: 2901-2911
  • Peer Reviewed
• [Journal Article] NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage Commitment (2012)
  • Author(s): Reynolds N, Latos P, Hynes-Allen A, Loos R, Leaford D, O'Shaughnessy A, Mosaku O, Signolet J, Brennecke P, Kalkan T, Costello I, Humphreys P, Mansfield W, Nakagawa K, Strouboulis J, Behrens A, Bertone P, Hendrich B
  • Journal Title: Cell Stem Cell Volume: 10巻5号 Pages: 538-594
  • Peer Reviewed
• [Journal Article] Expression of RASSF6 in kidney and the implication of RASSF6 and the Hippo signal in the sorbitol-induced apoptosis in renal proximal tubular epithelial cells (2012)
  • Author(s): Withanage K, Nakagawa K, Ikeda M, Kurihara H, Kudo T, Yang Z, Sakane A, Sasaki T, Hata Y
  • Journal Title: J. Biochem Volume: 152巻1号 Pages: 111-119
  • Peer Reviewed
• [Journal Article] A novel acetylation cycle of the transcription co-activator Yes-associated protein that is downstream of the Hippo signal is triggered in response to SN2 alkylating agents (2012)
  • Author(s): Hata S, Hirayama J, Kajiho H, Nakagawa K, Hata Y, Katada T, Furutani-Seiki M, Nishina H
  • Journal Title: J. Biol. Chem Volume: 287巻26号 Pages: 22089-22098
  • Peer Reviewed
• [Journal Article] NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment. (2012)
  • Author(s): Reynolds N., et al.
  • Journal Title: Cell Stem Cell Volume: 10 Issue: 5 Pages: 583-94
  • DOI: 10.1016/j.stem.2012.02.020
  • Peer Reviewed
• [Journal Article] A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents. (2012)
  • Author(s): Hata S.
  • Journal Title: Journal of Biological Chemistry Volume: 287 Issue: 26 Pages: 22089-22098
  • DOI: 10.1074/jbc.m111.334714
  • Peer Reviewed
• [Journal Article] Expression of RASSF6 in kidney and the implication of RASSF6 and the Hippo pathway in the sorbitol-induced apoptosis in renal proximal tubular epithelial cells (2012)
  • Author(s): Withanage, K., Nakagawa, K., Ikeda, M., Kurihara, H., Kudo, T., Yang, Z., Sakane, A., Sasaki, T. and Hata, Y
  • Journal Title: J. Biochem Volume: 152(1) Issue: 1 Pages: 111-119
  • DOI: 10.1093/jb/mvs056
  • NAID: 10031166119
  • Peer Reviewed
• [Journal Article] The RASSF3 candidate tumor suppressor induces apoptosis and G_1-S cell-cycle arrest via p53 (2012)
  • Author(s): Kudo T, Ikeda M, Nishikawa M, Yang Z, Ohno K, Nakagawa K, Hata Y
  • Journal Title: Cancer research誌 Volume: 72 Issue: 11 Pages: 2901-2911
  • DOI: 10.1158/0008-5472.can-12-0572
  • Peer Reviewed
• [Journal Article] Cancer susceptibility and embryonic lethality in Mobla/lb double-mutant mice. (2012)
  • Author(s): Nishio M.
  • Journal Title: J Clin Invest. Volume: 122 Issue: 12 Pages: 4505-4518
  • DOI: 10.1172/jci63735
  • Peer Reviewed
• [Journal Article] A cell based-assay to screen stimulators of the Hippo signal reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription (2011)
  • Author(s): Bao Y, Nakagawa K, Yang Z, Ikeda M, Withanage K, Ishigami-Yuasa M, Okuno Y, Hata S, Nishina H, Hata Y
  • Journal Title: J. Biochem Volume: 150巻2号 Pages: 199-208
  • Peer Reviewed
• [Journal Article] A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription (2011)
  • Author(s): Bao Y, et al.
  • Journal Title: Journal of Biochemistry Volume: 150 Issue: 2 Pages: 199-208
  • DOI: 10.1093/jb/mvr063
  • Peer Reviewed
• [Presentation] シンポジウム : 「ケミカルライブラリースクリーニング再考:アカデミアで意味あるケミカルライブラリースクリーニングを実現するために」 (2013)
  • Author(s): 中川健太郎、どど孝介世話人
  • Organizer: 第86回日本生化学会大会シンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2013-09-11
• [Presentation] 転写共役因子TAZを活性化する薬剤はマウスモデルにおける骨格筋の再生を促進する (2013)
  • Author(s): 中川健太郎、Yang Zeyu、畑裕
  • Organizer: 第86回日本生化学会大会シンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2013-09-11
• [Presentation] ケミカルライブラリースクリーニング再考：アカデミアで意味あるケミカルライ ブラリースクリーニングを実現するために (2013)
  • Author(s): 中川 健太郎、どど 孝介 オーガナイザー
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] ハイスループット細胞機能探索システムを用いたHippo pathway活性化化合物探索の試み (2011)
  • Author(s): 中川健太郎、Yang Zeyu、Kanchanamala Withanage、畑裕
  • Organizer: 第84回日本生化学会大会シンポジウム
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2011-09-21
• [Presentation] ハイスループット細胞機能探索システムを用いたHippo pathway活性化化合物探索の試み
  • Author(s): 中川 健太郎
  • Organizer: 日本生化学会
  • Place of Presentation: 京都国際会館 （京都）
• [Patent(Industrial Property Rights)] 筋形成促進剤、筋萎縮抑制剤、医薬組成物及びTAZ活性化剤 (2014)
  • 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: 2014-02-12
  • Overseas
• [Patent(Industrial Property Rights)] 筋形成促進剤、筋萎縮抑制剤、医薬組成物及びＴＡＺ活性化剤 (2014)
  • 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: 2014-02-12