Development of cell-response selective regulation of TGF-βsignaling

• Project/Area Number: 22390052
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: University of Yamanashi
• Principal Investigator: MIYAZAWA Keiji 山梨大学, 大学院・医学工学総合研究部, 教授 (40209896)
• Co-Investigator(Renkei-kenkyūsha): MOTIZUKI Mitsuyoshi 山梨大学, 大学院・医学工学総合研究部, 助教 (90174341) ; XU Zhaojun 山梨大学, 大学院・医学工学総合研究部, 助教 (00345703)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2011: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2010: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 細胞内シグナル伝達 / 細胞増殖因子 / シグナル伝達 / 細胞運動性 / Pin1 / ペプチドブロッカー

Research Abstract

Transforming growth factor (TGF)-β plays crucial roles in embryonic development and adult tissue homeostasis by eliciting various cellular responses in target cells. TGF- β signaling is principally mediated through receptor-activated Smad proteins, which regulate expression of target genes in cooperation with other DNA-binding transcription factors (Smad cofactors). In this study, we found that the basic helix-loop-helix transcription factor Olig1 is a Smad cofactor involved in TGF-β-induced cell motility. We also observed that cooperation of Smad2/3 with Olig1 is regulated by a peptidyl-prolyl cis/trans isomerase, Pin1. We further found that Olig1 interacts with the L3 loop ofSmad3. Using a synthetic peptide corresponding to the L3 loop of Smad3, we succeeded in selectively inhibiting TGF-β-induced cell motility. These findings may lead to a new strategy for selective regulation of TGF-β-induced cellular responses.

Research Products

• [Journal Article] Oligodendrocyte transcription factor 1 (Olig1) is a Smad cofactor involved in cell motility induced by transforming growth factor-β. (2013)
  • Author(s): Motizuki, M., Isogaya, K., Miyake, K., Ikushima, K., Kubota, T., Miyazono, K., Saitoh, M., and Miyazawa, K
  • Journal Title: J. Biol. Chem Volume: (in press)
  • Peer Reviewed
• [Journal Article] Basolateral BMP signaling in polarized epithelial cells (2013)
  • Author(s): Saitoh, M., Shirakihara, T., Fukasawa, A., Horiguchi, K., Sakamoto, K., Sugiya, H., Beppu, H., Fujita, Y., Morita, I., Miyazono, K., and Miyazawa, K
  • Journal Title: PLosONE Volume: 8
  • Peer Reviewed
• [Journal Article] Basolateral BMP signaling in polarized epithelial cells. (2013)
  • Author(s): Saitoh, M.
  • Journal Title: PLOS ONE Volume: in press
  • Peer Reviewed
• [Journal Article] Transcriptional and post-transcriptional regulation in TGF-β-mediated epithelial-mesenchymal transition. (2012)
  • Author(s): Saitoh,, M. and Miyazawa, K
  • Journal Title: J. Biochem Volume: 151 Pages: 563-571
  • NAID: 10031166097
  • Peer Reviewed
• [Journal Article] Structure of dominant-negative helix-loop-helix transcriptional regulator HHM representing the autoinhibition state (2012)
  • Author(s): Ishii, R., Seto, A., Isogaya, K., Seto, A., Koinuma, D., Watanabe, Y., Arisaka, F., Yaguchi, S., Ikushima, H., Dohmae, N., Miyazono, K., Miyazawa, K., Ishitani, R., and Nureki, O.
  • Journal Title: EMBO J Volume: 31 Pages: 2541-2552
  • Peer Reviewed
• [Journal Article] TGF-βdrives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP (2012)
  • Author(s): Horiguchi, K., Sakamoto, K., Koinuma, D., Semba, K., Inoue, A., Inoue, S., Fujii, H., Yamaguchi, A., Miyazawa,K., Miyazono K., and Saitoh, M
  • Journal Title: Oncogene Volume: 31 Pages: 3190-3201
  • Peer Reviewed
• [Journal Article] Transcriptional and post-transcriptional regulation in TGF-β-mediated epithelial-mesenchymal transition. (2012)
  • Author(s): Saitoh, M.
  • Journal Title: J. Biochem. Volume: 151 Issue: 6 Pages: 563-571
  • DOI: 10.1093/jb/mvs040
  • Peer Reviewed
• [Journal Article] Structure of a dominant-negative helix-loop-helix transcriptional regulator suggests mechanisms of autoinhibition (2012)
  • Author(s): Ishii R
  • Journal Title: EMBO Journal Volume: 31 Issue: 11 Pages: 2541-2552
  • DOI: 10.1038/emboj.2012.77
  • Peer Reviewed
• [Journal Article] Glioma-initiating cells retain their tumorigenicity through integration of the Sox axis and Oct4 (2011)
  • Author(s): Ikushima, H., Todo, T., Ino, Y., Takahashi, M., Saito, N., Miyazawa, K., and Miyazono, K
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 41434-41441
  • Peer Reviewed
• [Journal Article] RB1CC1 positively regulates TGF-βsignaling through modulation of Arkadia E3 ubiquitin ligase activity (2011)
  • Author(s): Koinuma, D., Shinozaki, M., Nagano, Y., Ikushima, H., Horiguchi, K., Goto, K., Chano, T., Saitoh, M., Imamura, T., Miyazono, K., and Miyazawa, K
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 32502-32512
  • Peer Reviewed
• [Journal Article] Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1 (2011)
  • Author(s): Inoue, Y., Iemura, S-i., Natsume, T., Miyazawa, K., and Imamura, T.
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 6311-6320
  • Peer Reviewed
• [Journal Article] TGF-βregulates FGF receptor isoform switching and epithelial-mesenchymal transition (2011)
  • Author(s): Shirakihara, T., Horiguchi, K., Miyazawa, K., Ehata, S., Shibata, T., Morita, I., Miyazono, K., and Saitoh, M
  • Journal Title: EMBO J Volume: 30 Pages: 783-795
  • Peer Reviewed
• [Journal Article] RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity (2011)
  • Author(s): Koinuma D
  • Journal Title: Journal of Biological Chemistry Volume: 286 Issue: 37 Pages: 32502-32512
  • DOI: 10.1074/jbc.m111.227561
  • Peer Reviewed
• [Journal Article] TGF-β derives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP (2011)
  • Author(s): 堀口華奈
  • Journal Title: Oncogene Volume: (掲載確定)(印刷中) Issue: 26 Pages: 3190-3201
  • DOI: 10.1038/onc.2011.493
  • Peer Reviewed
• [Journal Article] TGF-βregulates FGF receptor isoform switching and epithelial-mesenchvmal transition. (2011)
  • Author(s): Shirakihara, et al.
  • Journal Title: EMBO J. Volume: 30 Pages: 783-795
  • Peer Reviewed
• [Journal Article] Arkadia complexes with clathrin adaptor AP2 and regulates EGF signaling (2010)
  • Author(s): Mizutani, A., Saitoh, M., Imamura, T., Miyazawa, K., and Miyazono, K
  • Journal Title: J..Biochem Volume: 148 Pages: 733-741
  • NAID: 10027879992
  • Peer Reviewed
• [Journal Article] Smad7 inhibits transforming growth factor-βfamily type I receptors through two distinct modes of interaction (2010)
  • Author(s): Kamiya, Y., Miyazono, K., and Miyazawa, K
  • Journal Title: Biol. Chem Volume: 285 Pages: 30804-30813
  • Peer Reviewed
• [Journal Article] Smad7 inhibits transforming growth factor-βfamily type I receptors through two distinct modes of interaction (2010)
  • Author(s): Kamiya, et al.
  • Journal Title: J. Biol. Chem. Volume: 285 Pages: 30804-30813
  • Peer Reviewed
• [Journal Article] Identification of a phosphorylation site in c-Ski as serine 515 (2010)
  • Author(s): Nagata, et al.
  • Journal Title: J..Bioc.hem. Volume: 148 Pages: 423-427
  • Peer Reviewed
• [Presentation] TGF-βによる運動性促進に必須であるSmad-Olig1複合体形成はPin1によって制御される (2012)
  • Author(s): 望月光由、斉藤正夫、宮澤恵二
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] Pin1 regulates the cooperative action of Smad2/3 and Olig1 (2012)
  • Author(s): Keiji Miyazawa
  • Organizer: Ludwig Foundation TGF-βmeeting
  • Place of Presentation: Leiden, Nederland
  • Year and Date: 2012-08-29
• [Presentation] Selective regulation of TGF-β-induced cellular responses: TGF-βFamily (2012)
  • Author(s): Keiji Miyazawa
  • Organizer: Signal Network in Biologocal Functions The 1st International Symposium by JSPS Core-to-Core Program "Cooperative International Framework in TGF-βFamily Signaling"
  • Place of Presentation: Tokyo
  • Year and Date: 2012-01-23
• [Presentation] Selective regulation of TGF-β-induced cellular responses (2012)
  • Author(s): Keiji Miyazawa
  • Organizer: TGF-β Family : Signal Network in Biologocal Functions The 1st International Symposium by JSPS Core-to-Core Program "Cooperative International Framework in TGF-β Family Signaling"
  • Place of Presentation: 東京大学小柴記念ホール(東京都)(招待講演)
  • Year and Date: 2012-01-23
• [Presentation] Smad共役因子Olig1はTGF-βにより誘導される細胞運動を制御する (2011)
  • Author(s): 望月光由、齋藤正夫、宮澤恵二
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Smad共役因子Olig1はTGF-βにより誘導される細胞運動を制御する (2011)
  • Author(s): 望月光由
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-04
• [Presentation] Olig1 is a Smad cofactor that mediates TGF-β-induced cell motility (2011)
  • Author(s): Keiji Miyazawa
  • Organizer: Ludwig Foundation TGF-βmeeting
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2011-08-18
• [Presentation] How to achieve cellular-response-selective regulation of TGF-βsignaling (2011)
  • Author(s): Keiji Miyazawa
  • Organizer: KSBMB
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-05-17
• [Presentation] Olig1 is an essential transcription factor for the TGF-β-induced cell migration (2010)
  • Author(s): Mitsuyoshi Motizuki, Masao Saitoh, and Keiji Miyazawa
  • Organizer: BMB2010
  • Place of Presentation: Kobe
  • Year and Date: 2010-12-07
• [Presentation] The role of Smad-Olig1 transcription complex in TGF-βsignaling (2010)
  • Author(s): Keiji Miyazawa
  • Organizer: Ludwig Foundation TGF-βmeeting
  • Place of Presentation: Leiden, Nederland
  • Year and Date: 2010-09-02
• [Presentation] An-Id-like molecule, Maid, is a cellular-response selective regulator of TGF-βsignaling (2010)
  • Author(s): Keiji Miyazawa
  • Organizer: 藤原セミナー
  • Place of Presentation: 苫小牧
  • Year and Date: 2010-07-15
• [Presentation] Pin1 regualtes the cooperative action of Smad2/3 and Olig1
  • Author(s): Keiji Miyazawa
  • Organizer: Ludwig foundation TGF-beta meeting
  • Place of Presentation: Leiden University Medical Center (Leiden, Holland)
• [Presentation] TGF-β enhances cell migration through the Pin1-regualted Smad-Olig1 transcriptional complex.
  • Author(s): 望月光由
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市教育文化会館（札幌市）
• [Book] がん増殖と悪性化の分子機構 (2012)
  • Author(s): 澤恵二
  • Total Pages: 13
  • Publisher: 化学同人
• [Remarks]
  • URL: http://www.med.yamanashi.ac.jp/basic/bioche02/bioch2.html
• [Remarks] 生化学講座第２教室
  • URL: http://www.med.yamanashi.ac.jp/basic/bioche02/bioch2.html
• [Remarks]
  • URL: http://www.med.yamanashi.ac.jp/basic/bioche02/