Studies on a role of a crosslinking enzyme, transglutaminase in pathogenesis of liver diseases

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390215
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: KOJIMA Soichi The Institute of Physical and Chemical Research, 分子リガンド生物研究チーム, チームリーダー (10202061)
• Co-Investigator(Kenkyū-buntansha): YAMAGUCHI Kanji 京都府立医科大学, 医学部付属病院, 研究員 (50381950) ; KOSE Shingo 独立行政法人理化学研究所, 今本細胞核機能研究室, 専任研究員 (90333278)
• Co-Investigator(Renkei-kenkyūsha): MATSUURA Tomokazu 東京慈恵会医科大学, 医学研究科, 准教授 (30199749)
• Project Period (FY): 2008 – 2010
• Keywords: Sp1, c-Met,アポトーシス / アルコール脂肪性肝炎 / トランスグルタミナーゼ / 架橋反応 / 小胞体ストレス / 非アルコール脂肪性肝炎

Research Abstract

We demonstrated that upon injury, a protein crosslinking enzyme, transglutaminase translocates into the nucleus via its C-domain, crosslinks and inactivates Sp1 transcription factor, which results in the downregulation of the expression levels in c-Met, leading to caspase-independent hepatic cell death as well as fibrosis of the liver in both animal models and patients. We started screening of a unique compound that specifically inhibits nuclear translocation of transglutaminase.

Research Products

• [Journal Article] Free fatty acids induce transglutami- nase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways (2011)
  • Author(s): Kuo T.-F., Tatsukawa H., Matsuura T., Nagatsuma K., Hirose S., Kojima S
  • Journal Title: J.Cell Physiol. (in press)
  • Peer Reviewed
• [Journal Article] Brain infarction correlates more closely with acrolein than with reactive oxygen species (2011)
  • Author(s): Saiki R., Park H., Ishii I., Yoshida M., Nishimura K., Toida T., Tatsukawa H., Kojima S., Ikeguchi Y., Pegg A.E., Kashiwagi K., Igarashi K.
  • Journal Title: Biochem.Biophys.Res.Commun. 404(4) Pages: 1044-1049
  • Peer Reviewed
• [Journal Article] Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells (2011)
  • Author(s): Tatsukawa H., Sano T., Fukaya Y., Ishibashi N., Watanabe M., Okuno M., Moriwaki H., Kojima S.
  • Journal Title: Molecular Cancer 10(1) Pages: 4(11)
  • Peer Reviewed
• [Journal Article] In situ detection of active transglutaminases for keratinocyte type (TGase 1) and tissue type (TGase 2) using fluorescence-labeled highly reactive substrate peptides (2011)
  • Author(s): Itoh M., Kawamoto T., Tatsukawa T., Kojima S., Yamanishi K., Hitomi K.
  • Journal Title: J.Histochem.Cytochem. 59(2) Pages: 180-187
  • Peer Reviewed
• [Journal Article] Induction of crosslinking and silencing of Sp1 by transglutaminase during liver injury in ASH and NASH via different ER stress pathways (2010)
  • Author(s): Kojima S., Kuo T.-F., Tatsukawa H., Hirose S.
  • Journal Title: Digestive Diseases 28(6) Pages: 715-721
• [Journal Article] Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-y (2010)
  • Author(s): Mukhopadhyay B., Liu J. Osei-Hyiaman D., Godlewski G., Mukhopadhyay P., Wang L., Jeong W., Gao B., Duester G., Mackie K., Kojima S., Kunos G.
  • Journal Title: J.Biol.Chem. 285(25) Pages: 19002-19011
  • Peer Reviewed
• [Journal Article] Recent advances in understanding of roles of transglutaminase in alcoholic steatohepatitis (2010)
  • Author(s): Tatsukawa H., Kojima S.
  • Journal Title: Cell Biol.Int. 34(3) Pages: 325-334
  • Peer Reviewed
• [Journal Article] Role of transglutaminase 2 in liver injury via crosslinking and silencing of transcription factor, Sp1. (2009)
  • Author(s): Tatsukawa H., Fukaya Y., Frampton G., Martinez-Fuentes A., Suzuki K., Kuo T.-F., Nagatsuma K., Shimokado K., Okuno M., Wu J., lismaa S., Matsuura T., Tsukamoto H., Zern M.A., Graham R.M., Kojima S.
  • Journal Title: Gastroenterology 136(5) Pages: 1783-1795, cover page
  • Peer Reviewed
• [Journal Article] TGF-β regulates expression of KLF6 and its splice variants, and promotes cooperative transactivation of common target genes through a Smad3-Sp1-KLF6 interaction (2009)
  • Author(s): Botella L.M., Rodriguez-Sanz F., Komi Y., Fernandez-L A., Varela E., Garrido-Martin E.M., Narla G., Friedman S.L., Kojima S.
  • Journal Title: Biochem.J. 419(2) Pages: 485-495
  • Peer Reviewed
• [Journal Article] アルコール性肝障害の新規肝細胞死誘導経路の発見 (2009)
  • Author(s): 辰川英樹、小嶋聡一
  • Journal Title: バイオサイエンスとインダストリー 67(8) Pages: 423-427
• [Presentation] Induction of crosslinking and silencing of Sp1 by transglutaminase during liver injury in ASH and NASH via different ER stress pathways (2010)
  • Author(s): Kojima S
  • Organizer: 5th Int Meeting on Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis
  • Place of Presentation: Freiburg, Germany
  • Year and Date: 2010-10-05
• [Presentation] Induction of transglutaminase 2 during the pathogenesis of both alcoholic steatohepatitis and non-alcoholic steatohepatitis (2010)
  • Author(s): Kojima S.
  • Organizer: 2010 ISBRA World Congress
  • Place of Presentation: Paris, France
  • Year and Date: 2010-09-15
• [Presentation] Crosslinking and silencing of Sp1 by transglutaminase during liver injury (2010)
  • Author(s): Kojima S.
  • Organizer: 1^<st> Gordon Research Conference on "Transgluta- minases in Human Disease Processes"
  • Place of Presentation: Davidson, NC, USA
  • Year and Date: 2010-07-19
• [Presentation] Induction of protein crosslinking enzyme, transglutaminase, during pathogenesis of non-alcoholic steatohepatitis (2009)
  • Author(s): Kojima S., et al.
  • Organizer: 4th Int Sympo on Alcoholic liver and pancreatic Disease and cirrhosis
  • Place of Presentation: Hurghada, Egypt
  • Year and Date: 20091008-20091009
• [Presentation] A novel hepatic apoptosis pathway in the injured liver via crosslinking and inactivation of transcription factor, Sp1 by tissue transglutaminase (2008)
  • Author(s): Tatsukawa H., et al.
  • Organizer: 59th Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2008-11-01
• [Book] 肝疾患Review 2010～2011 (2010)
  • Author(s): 小嶋聡一,辰川英樹
  • Total Pages: 231-235
  • Publisher: 日本メディカルセンター
• [Book] 入門ケミカルバイオロジー (2008)
  • Author(s): 長田裕之,小嶋聡一, 他
  • Total Pages: 189
  • Publisher: 株式会社オーム社
• [Remarks] ホームページ等
• [Remarks] 理研プレスリリース「タンパク質の架橋反応が細胞死を招き、アルコール性肝障害に-アルコール性障害の肝臓で繰り広げられる新しい肝細胞死のメカニズムを発見-」2009年5月1日
  • URL: http://www.riken.go.jp/r-world/info/release/press/2011/index.html
• [Remarks] 日刊工業新聞「独創研究集団 理研の最前線 アルコール性肝障害の新しい病態形成機構 肝細胞死経路を発見 疾患の新診断法開発」2009年9月21日
• [Remarks] 理研ニュース2009年7月号「アルコール性肝障害における肝細胞死の新しい経路を発見」2009年7月6日
• [Remarks] ヤフージャパンニュース「飲みすぎによる肝障害のメカニズムを解明」2009年5月12日
• [Remarks] ニッケイネット「理化学研究所、アルコール性肝障害の新たな分子メカニズムを解明」2009年5月1日