The analysis for the regulation of IEC differentiation by the switching mechanism of GSK3

• Project/Area Number: 24590935
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TSUCHIYA Kiichiro 東京医科歯科大学, 医歯(薬)学総合研究科, 寄附講座准教授 (40376786)
• Co-Investigator(Kenkyū-buntansha): WATANABE Mamoru 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Atoh1 / GSK3 / TNFα / 蛋白安定機構 / サイトカイン

Outline of Final Research Achievements

We have clarified that β-catenin and Atoh1 regulated by GSK-3βcontrol not only cell differentiation and proliferation but also cell fate under various kinds of cell signaling to change the target protein of GSK-3β. In this study, we aimed to identify the adapter protein which is specific for GSK3-Atoh1 complex and understand GSK3 control structure in each signal via GSK3. Finally we aimed to elucidate the differentiation system of the intestinal epithelia cell.

Research Products

• [Journal Article] Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. (2015)
  • Author(s): Oshima H, Nakayama M, Han TS, Naoi K, Ju X, Maeda Y, Robine S, Tsuchiya K, Sato T, Sato H, Taketo MM, Oshima M.
  • Journal Title: Cancer Res. Volume: 75 Issue: 4 Pages: 766-776
  • DOI: 10.1158/0008-5472.can-14-2036
  • NAID: 120005593962
  • Peer Reviewed / Open Access
• [Journal Article] Associations of HLA class I alleles in Japanese patients with Crohn's disease. (2015)
  • Author(s): 102)Oryoji D, Hisamatsu T, Tsuchiya K, Umeno J, Ueda S, Yamamoto K, Matsumoto T, Watanabe M, Hibi T, Sasazuki T.
  • Journal Title: Genes Immun. Volume: 16 Issue: 1 Pages: 54-56
  • DOI: 10.1038/gene.2014.61
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fluorescent labelling of intestinal epithelial cells reveals independent long-lived intestinal stem cells in a crypt. (2014)
  • Author(s): N. Horita, K. Tsuchiya, R. Hayashi, K. Fukushima, S. Hibiya, M. Fukuda, Y. Kano, T. Mizutani, Y. Nemoto, S. Yui, R. Okamoto, T. Nakamura, M. Watanabe
  • Journal Title: Biochem Biophys Res Commun Volume: 454 Issue: 4 Pages: 493-499
  • DOI: 10.1016/j.bbrc.2014.10.091
  • Peer Reviewed / Open Access
• [Journal Article] RIPK3 regulates p62-LC3 complex formation via the caspase-8-dependent cleavage of p62. (2014)
  • Author(s): Y. Matsuzawa , S. Oshima, Y. Nibe, M.Kobayashi, C. Maeyashiki, Y. Nemoto, T. Nagaishi, R. Okamoto R, K. Tsuchiya, T. Nakamura, M. Watanabe.
  • Journal Title: Biochem Biophys Res Commun Volume: 456(1) Issue: 1 Pages: 298-304
  • DOI: 10.1016/j.bbrc.2014.11.075
  • Peer Reviewed / Open Access
• [Journal Article] Distinct expression patterns of Notch ligands, Dll1 and Dll4, in normal and inflamed mice intestine. (2014)
  • Author(s): Shimizu H, Okamoto R, Ito G, Nakata T, Suzuki K, Murano T, Mizutani T, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M.
  • Journal Title: PeerJ Volume: 2 Pages: e370-e370
  • DOI: 10.7717/peerj.370
  • Peer Reviewed / Open Access
• [Journal Article] Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells (2014)
  • Author(s): Murano T, Okamoto R, Ito G, Nakata T, Hibiya S, Shimizu H, Fujii S, Kano Y, Mizutani T, Yui S, Akiyama-Morio J, Nemoto Y, Tsuchiya K, Nakamura T, Watanabe M
  • Journal Title: Biochem Biophys Res Commun Volume: 443 Issue: 3 Pages: 840-846
  • DOI: 10.1016/j.bbrc.2013.12.061
  • Peer Reviewed / Open Access
• [Journal Article] Lineage-specific expression of Bestrophin-2 and Bestrophin-4 in human intestinal epithelial cells. (2013)
  • Author(s): Ito G, Okamoto R, Nakamura T, Watanabe M et al
  • Journal Title: PloS One. Volume: 8 Issue: 11 Pages: e79693-e79693
  • DOI: 10.1371/journal.pone.0079693
  • Peer Reviewed
• [Journal Article] IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice. (2013)
  • Author(s): Takahara M, Nemoto Y, Oshima S, Matsuzawa Y, Kanai T, Okamoto R, Tsuchiya K, Nakamura T, Yamamoto K, Watanabe M.
  • Journal Title: Immunol Lett. Volume: 156 Issue: 1-2 Pages: 82-93
  • DOI: 10.1016/j.imlet.2013.09.001
  • NAID: 120005468269
  • Peer Reviewed
• [Journal Article] Th1/Th17-Mediated Interstitial Pneumonia in Chronic Colitis Mice Independent of Intestinal Microbiota. (2013)
  • Author(s): Nemoto Y, Watanabe M et al
  • Journal Title: J Immunol. Volume: 190 Issue: 12 Pages: 6616-6625
  • DOI: 10.4049/jimmunol.1202930
  • Peer Reviewed
• [Journal Article] 消化管幹細胞と消化器がん幹細胞 (2013)
  • Author(s): 土屋輝一郎
  • Journal Title: 日本内科学会雑誌 Volume: 102 Pages: 2273-2278
  • NAID: 10031202663
• [Journal Article] 【特集：機能性消化管障害(FGID):診断と治療の進歩】I. FGIDの基本的知識 4. 感染症や腸内細菌の意義（免疫学的異常について） (2013)
  • Author(s): 土屋輝一郎
  • Journal Title: 日本内科学会雑誌 Volume: 102 Pages: 25-31
• [Journal Article] The acquisition of malignant potential in colon cancer is regulated by the stabilization of Atonal homolog 1 protein. (2013)
  • Author(s): Kano Y
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 432 Issue: 1 Pages: 175-181
  • DOI: 10.1016/j.bbrc.2013.01.034
  • Peer Reviewed / Open Access
• [Journal Article] Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4+ memory T cells. (2013)
  • Author(s): Nemoto Y, Nakamura T, Watanabe M et al
  • Journal Title: Gut. Volume: 62 Issue: 8 Pages: 1142-1152
  • DOI: 10.1136/gutjnl-2012-302029
  • Peer Reviewed
• [Journal Article] Modifiedsingle-operator method for double-balloon endoscopy (2012)
  • Author(s): Araki A, Suzuki S, Tsuchiya K, OshimaS, Okada E, Watanabe M
  • Journal Title: Dig Endosc Volume: 24(6) Issue: 6 Pages: 470-4
  • DOI: 10.1111/j.1443-1661.2012.01321.x
  • Peer Reviewed
• [Journal Article] Endoscopic ultrasound with double-balloon endoscopy for the diagnosis of inverted Meckel'sdiverticulum: a case report (2012)
  • Author(s): Araki A, Tsuchiya K, Oshima S, Okada E,Suzuki S, Akiyama JM, Fujii T, OkamotoR, Watanabe M
  • Journal Title: J Med Case Rep Volume: 6(1) Issue: 1 Pages: 328-328
  • DOI: 10.1186/1752-1947-6-328
  • Peer Reviewed
• [Presentation] The Acquisition of Cancer Stemness by Atoh1 in Colitis Associated Cancer (2015)
  • Author(s): Kiichiro Tsuchiya, Keita Fukushima, Mamoru Watanabe
  • Organizer: 8th Annual World Congress of Regenerative Medicine & Stem Cells
  • Place of Presentation: 釜山（韓国）
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] Innate immune spiral of intestinal epithelial cells by the long-term inflammation. (2014)
  • Author(s): Tsuchiya K, Hibiya S, Watanabe M
  • Organizer: The 73rd Annual Meeting of the Japanese Cancer Association.
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-25
• [Presentation] Molecular mechanism in the pathogenesis of the colitis-associated colorectal cancer (2014)
  • Author(s): Tsuchiya K
  • Organizer: The 32th Annual Meeting of Japanese Society for Cytoprotection & Cytobiology
  • Place of Presentation: Kyoto, Japan
  • Invited
• [Presentation] Live imaging of single cell reveals single stem cell dynamics in an organoid derived from murine small intestine. (2013)
  • Author(s): Horita N, Tsuchiya K, Hibiya S, Fukushima K, Kano Y, Xiu Zheng, Okamoto R, Nakamura T , Watanabe M
  • Organizer: DDW2013
  • Place of Presentation: Orland, USA
• [Presentation] Stabilization of Atoh1 protein by TNF-α in colitic cancer might acquire the cancer stemness (2013)
  • Author(s): Tsuchiya K, Fukushima K, Kano Y, Hibiya S, Horita N, Xiu Zheng, Okamoto R,Nakamura T, Watanabe M
  • Organizer: DDW2013
  • Place of Presentation: Orland, USA
• [Presentation] Atoh1 protein stabilization acquired cancer stem cell phenotype and niche in colon cancer (2013)
  • Author(s): Kano Y, Tsuchiya K, Okamoto R, Nakamura T, Watanabe M
  • Organizer: GI Research Academy 2013
  • Place of Presentation: 京都
• [Presentation] Atoh1proteinstabilizationacquiredcancerstemcell phenotype and niche in colon cancer. (2013)
  • Author(s): Kano Y, Tsuchiya K, Watanabe M
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Cancer Stemness In Mucinous Colon Cancer. (2013)
  • Author(s): Tsuchiya K, Kano Y, Watanabe M
  • Organizer: BIT's 6th Annual World Congress of Regenerative Medicine & Stem Cells-2013
  • Place of Presentation: 大連、中国
  • Invited
• [Presentation] 消化管幹細胞と消化器癌幹細胞 (2013)
  • Author(s): 土屋輝一郎
  • Organizer: 第110回 日本内科学会講演会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 全小腸マッピング生検検体を用いた網羅的遺伝子発現解析によるクローン病特異的遺伝子の同定 (2013)
  • Author(s): 堀田伸勝、土屋輝一郎、渡辺 守
  • Organizer: 第85回 日本消化器内視鏡学会総会
  • Place of Presentation: 京都
• [Presentation] 炎症関連大腸がんにおける悪性形質獲得機構解析 (2013)
  • Author(s): 土屋輝一郎
  • Organizer: がん研究分野の特性等を踏まえた支援活動 公開シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] Atoh1発現大腸癌における幹細胞形質獲得とニッチ形成 (2013)
  • Author(s): 加納嘉人、土屋輝一郎、渡辺 守
  • Organizer: JDDW2013
  • Place of Presentation: 東京
• [Presentation] 白血球除去療法（LCAP）による潰瘍性大腸炎の治療戦略 (2013)
  • Author(s): 土屋輝一郎
  • Organizer: JDDW2013
  • Place of Presentation: 東京
  • Invited
• [Presentation] 全小腸マッピング生検によるクローン病病態解析 (2013)
  • Author(s): 土屋輝一郎、堀田伸勝、林 亮平、日比谷秀爾、福島啓太、加納嘉人、渡辺 守
  • Organizer: 第51回 小腸研究会
  • Place of Presentation: 名古屋
• [Presentation] The acquisition of cancer stemness in colon cancer by the Atoh1 protein stabilization. (2012)
  • Author(s): Kano Y, Tsuchiya K, Horita N, Zheng X, Okamoto R, Nakamura T, Watanabe M
  • Organizer: DDW2012
  • Place of Presentation: San Diego, USA
• [Presentation] Flagellin response via TLR5 on basolateral membrane of primary intestinal epithelial cells is regulated by Notch signaling. (2012)
  • Author(s): Tsuchiya K, Zheng X, Kano Y, Okamoto R, Nakamura T, Watanabe M
  • Organizer: DDW2012
  • Place of Presentation: San Diego, USA
• [Presentation] The stabilization of Atoh1 protein in colon cancer acquires cancer stemness and chemoresistance. (2012)
  • Author(s): Tsuchiya K, Kano Y, Mizutani T, Yui S, Nakamura T, Watanabe M
  • Organizer: 第10回 幹細胞シンポジウム.
  • Place of Presentation: 淡路島
• [Presentation] The stabilization of Atoh1 protein in colitic cancer induces cancer stemness and chemoresistance. (2012)
  • Author(s): Tsuchiya K, Kano Y, Watanabe M
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Intestinal stem cells and cancer stem cells. (2012)
  • Author(s): Tsuchiya K
  • Organizer: Cancer Stem Cell Symposium
  • Place of Presentation: 福岡
  • Invited
• [Presentation] 大腸における幹細胞維持とがん幹細胞発現機構 (2012)
  • Author(s): 土屋輝一郎、加納嘉人、中村哲也、渡辺 守
  • Organizer: 第44回日本臨床分子形態学会総会・学術集会
  • Place of Presentation: 高知
  • Invited