Analysis of hepatocarcinogenesis due to monoubiquitylation of gankyrin that is one of the proteasome-interacting proteins

• Project/Area Number: 20590773
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: HIGASHITSUJI Hiroaki Kyoto University, 医学研究科, 助教 (60281094)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: プロテアソーム / ガンキリン / モノユビキチン / 肝細胞癌 / 原発性肝癌 / 26Sプロテアソーム / PIP / 肝癌 / ユビキチン

Research Abstract

Gankyrin is monoubiquitylated at specific lysine residue posttranslationally. However, other ubiquitin like modifiers, that is, NEDD8, SUMO1-4, ISG15, or URM1, does not bind to gankyrin. Monoubiquitylation of oncogenic gankyrin induces hepatic cell transformation more stimulatedly than wild type nonmodified gankyrin posttranslationally. In hepatoma cell lines, monoubiquitylated gankyrin binds to S6 ATPase and MDM2. Nevertheless, monoubiquitylated gankyrin targets more effectively pRB than p53 toward MDM2 E3 lubiquitin ligase activity. Some of gankyrin monoubiquitylation systems consisting of E1, E2, E3, E4, and DUB will become targets of anti-cancer drugs.

Research Products

• [Journal Article] MDM2 is a novel E3 ligase for HIV-1 Vif. (2009)
  • Author(s): Izumi T, Takaori-Kondo A, Shirakawa K, Higashitsuji H, Itoh K, Io K, Matsui M, Iwai K, Kondoh H, Sato T, Tomonaga M, Ikeda S, Akari H, Koyanagi Y, Fujita J, Uchiyama T.
  • Journal Title: Retrovirology 6 Pages: 1-10
  • NAID: 120004770229
  • Peer Reviewed
• [Journal Article] MDM2 is a novel E3 ligase for HIV-1 Vif. (2009)
  • Author(s): Izumi T
  • Journal Title: Retrovirology 6 Pages: 1-10
  • Peer Reviewed
• [Journal Article] MDM2 is a novel E3 ligase for HIV-1 Vif. (2009)
  • Author(s): Izumi T, Takari-Kondo A. Shirakawa K, Higashitsuji H, Itoh K. lo K, Matsui M, Iwai K, Kondoh H, Sato T, Tomonaga M, Ikeda S, Akari H, Koyanagi Y, Fujita J, Uchiyaima T.
  • Journal Title: Retrovirology 6 Pages: 1-10
  • NAID: 120004770229
  • Peer Reviewed
• [Journal Article] Association of gankyrin protein expression with early clinical stages and IGFBP-5 expression in human hepatocellular carcinoma. (2008)
  • Author(s): Umemura A, Itoh Y, Itoh K, Yamaguchi K, Nakajima T, Higashitsuji H, Onoue H, Fukumoto M, Okanoue T, Fujita J.
  • Journal Title: Hepatology 47(2) Pages: 493-502
  • Peer Reviewed
• [Journal Article] Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance. (2008)
  • Author(s): Ortiz CM, Ito T, Tanaka E, Tsunoda S, Nagayama S, Sakai Y, Higashitsuji H, Fujita J, Shimada Y.
  • Journal Title: Int J Cancer 122 Pages: 325-332
  • Peer Reviewed
• [Journal Article] Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma. (2008)
  • Author(s): Umemura, A
  • Journal Title: Hepatology 47 Pages: 493-502
  • Peer Reviewed
• [Journal Article] Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance. (2008)
  • Author(s): Ortiz, C.M.
  • Journal Title: Int J Cancer 122 Pages: 325-332
  • Peer Reviewed
• [Journal Article] Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma. (2008)
  • Author(s): Umemura, A., Itoh, Y., Itoh, K., Yamaguchi, K., Nakajima, T., Higashitsuji, H., Oaoue H., Fukumoto, M, Okanoue, T., Fujita, J.
  • Journal Title: Hepatology 47 Pages: 493-502
  • Peer Reviewed
• [Journal Article] Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance. (2008)
  • Author(s): Ortiz, C. M., Ito, T., Tanaka, E., Tsunoda, S., Nagayama, S., Sakai, Y., Higashitsuji, H., Fujita, J., Shimada, Y.
  • Journal Title: Int J Cancer 122 Pages: 325-332
  • Peer Reviewed
• [Presentation] 肝癌で高発現するCIRP (cold-inducible RNA binding protein)は腫瘍細胞の浸潤能を亢進させる (2010)
  • Author(s): 東辻宏明
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: 山形市、ホテルメトロポリタン山形
  • Year and Date: 2010-05-28
• [Presentation] 肝癌で高発現するCIRP(cold-inducible RNA binding protein)は腫瘍細胞の浸潤能を亢進させる (2010)
  • Author(s): 東辻宏明
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: 山形市ホテルメトロポリタン山形
  • Year and Date: 2010-05-28
• [Presentation] NEDD8化ガンキリンを介したMDM2の基質特異性の変化 (2009)
  • Author(s): 東辻宏明
  • Organizer: 第95回日本消化器病学会
  • Place of Presentation: ロイトン札幌、札幌市
  • Year and Date: 2009-05-09
• [Presentation] NEDD88ガンキリンを介たMDM2の基質特異性の変化 (2009)
  • Author(s): 東辻宏明
  • Organizer: 第95回日本消化器病学会
  • Place of Presentation: ロイトン札幌、札幌市
  • Year and Date: 2009-05-09
• [Presentation] 肝癌で過剰発現するがん遺伝子ガンキリンはNFkappaB (RelA)と結合しその転写活性化能を抑制する (2008)
  • Author(s): 東辻宏明
  • Organizer: 第44回日本肝臓学会
  • Place of Presentation: 松山市、愛媛県
  • Year and Date: 2008-06-06
• [Presentation] 肝癌で過剰発現するがん遺伝子ガンキリンはNFkappaB(RelA)と結合しその転写活性化能を抑制する (2008)
  • Author(s): 東辻宏明
  • Organizer: 第44回日本肝臓学会
  • Place of Presentation: 松山市、愛媛県
  • Year and Date: 2008-06-06