Mechanism of carcinogenesis by dysregulation of cell cycle via abnormal ubiquitin-mediated proteolysis

• Project/Area Number: 23689074
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Morphological basic dentistry
• Research Institution: The University of Tokushima (2012-2013); Hiroshima University (2011)
• Principal Investigator: KUDO Yasusei 徳島大学, ヘルスバイオサイエンス研究部, 准教授 (50314753)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥27,560,000 (Direct Cost: ¥21,200,000、Indirect Cost: ¥6,360,000); Fiscal Year 2013: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2012: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2011: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: 細胞周期 / ユビキチン分解 / 癌 / APC/Cユビキチンリガーゼ複合体 / 細胞分裂 / APC/C / Geminin / Aurora-A

Research Abstract

In the present study, we focused on the APC/C ubiquitin ligase complex that is involved in the degradation of cell division-related proteins. We found that the speed of ubiquitylation process is dependent on the sequence of degradation domain. Moreover, we found that one of the APC/C substrate, geminin is phosphorylated at mitosis, and this phosphorylation leads to DNA synthesis by preventing from APC/C-mediated proteolysis at mitosis. We also found that knockdown of Emi1 which is an APC/C inhibitor enhances the sensitivity of anti-cancer drug. These findings indicate that ubiquitin-mediated proteolysis via APC/C ubiquitin ligase is essential to cell cycle regulation and suggest that abnormal regulation of APC/C-mediated proteolysis may be involved in carcinogenesis.

Research Products

• [Journal Article] Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis. (2013)
  • Author(s): Tsunematsu T, Takihara Y, Ishimaru N, Pagano M, Takata T, Kudo Y.
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1885-1885
  • DOI: 10.1038/ncomms2859
  • Peer Reviewed
• [Journal Article] Selective enhancing effect of Early mitotic inhibitor 1 depletion on the sensitivity of doxorubicin or X-ray treatment in human cancer cells (2013)
  • Author(s): Shimizu, N., Nakajima, N.I., Tsunematsu, T., Ogawa, I., Kawai, H., Hirayama, R., Fujimori, A., Okayasu, R., Ishimaru, N., Takata, T., Kudo, Y.
  • Journal Title: J Biol Chem Volume: 288 Pages: 17238-17252
  • Peer Reviewed
• [Journal Article] Selective enhancing effect of Early mitotic inhibitor 1 depletion on sensi tivity of doxorubicin. (2013)
  • Author(s): Shimizu N, Nakajima NI, Tsunematsu T, Ogawa I, Kawai H, Hirayama R, Fujimori A, Yamada A, Okayasu R, Ishimaru N, Takata T, Kudo Y.
  • Journal Title: Journal of Biological Chemistry Volume: 288 Issue: 24 Pages: 17238-17252
  • DOI: 10.1074/jbc.m112.446351
  • Peer Reviewed
• [Journal Article] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis. (2013)
  • Author(s): Tsunematsu T, et al.
  • Journal Title: Nature Communications Volume: 印刷中
  • Peer Reviewed
• [Journal Article] The Cyclin F-Ribonucleotide Reductase M2 axis controls genome integrity and DNA repair (2012)
  • Author(s): D'Angiolella, V., Donate, V., Forrester, F. M., Jeong, Y. T., Pellacani, C., Kudo, Y., Saraf, A., Florens, L., Washburn, M. P., Pagano, M.
  • Journal Title: Cell Volume: 149 Pages: 1023-1034
  • Peer Reviewed
• [Journal Article] Overexpression of Receptor for Hyaluronan-Mediated Motility (RHAMM) in MC3T3-E1 induces the proliferation and differentiation through phosphorypation of ERK1/2 (2012)
  • Author(s): Hatano, H., Shigeishi, H., Kudo, Y., Higashikawa, K., Tobiume, K., Takata, T., Kamata, N.
  • Journal Title: J Bone Miner Metabol Volume: 30(3) Pages: 293-303
  • Peer Reviewed
• [Journal Article] The Cyclin F-Ribonucleotide Reductase M2 axis controls genome integrity and DNA repair. (2012)
  • Author(s): D'Angiolella V, et al.
  • Journal Title: Cell Volume: 149 Pages: 1023-1034
  • Peer Reviewed
• [Journal Article] The Cyclin F-Ribonucleotide Reductase M2 axis controls genome integrity and DNA repair (2012)
  • Author(s): D'Angiolella, V., Donate, V., Forrester, F.M., Jeong, Y.T., Kudo, Y., et al
  • Journal Title: Cell Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Overexpression of Receptor for Hyaluronan-Mediated Motility (RHAMM) in MC3T3-E1 induces the proliferation and differentiation through phosphorypation of ERK1/2 (2012)
  • Author(s): Hatano, H., Shigeishi, H., Kudo, Y., et al
  • Journal Title: J Bone Miner Metabol Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] MMP-10/stromelysin-2 promotes invasion of head and neck cancer (2011)
  • Author(s): Deraz, E.M., Kudo, Y., Yoshida, M., Tani, H., Tsunematsu, T., Siriwardena, B.S.M.S., Kiekhaee, M.R., Qi, G., Iizuka, S., Ogawa, I., Campisi, G., Lo Muzio, L., Abiko, Y., Kikuchi, A., Takata, T.
  • Journal Title: PLoS ONE Volume: 6(10)
  • NAID: 120005300499
  • Peer Reviewed
• [Journal Article] SCF^<ßTrcp>mediates stress-induced Cdc25B ubiquitylation through cooperation of an atypical consensus sequence and PEST (2011)
  • Author(s): Uchida, S., Watanabe, N., Kudo, Y., Yoshioka, K., Matsunaga, T., Ishizuka, Y., Nakagama, H., Poon, R.Y.C., Yamashita, K.
  • Journal Title: J Cell Sci Volume: 124 Pages: 2816-25
  • Peer Reviewed
• [Journal Article] miR-22 represses cancer progression by inducing celular senescence (2011)
  • Author(s): Xu, D., Takeshita, F., Hino, Y., Fukunaga, S., Kudo, Y., Tamaki, A., Takata, T., Shimamoto, A., Ochiya, T., Tahara, H.
  • Journal Title: J Cell Biol Volume: 193(2) Pages: 409-24
  • Peer Reviewed
• [Journal Article] MMP-10/stromelysin-2 promotes invasion of head and neck cancer (2011)
  • Author(s): Deraz, E.M., Kudo, Y., et al
  • Journal Title: PLoS ONE Volume: 6
  • NAID: 120005300499
  • Peer Reviewed
• [Journal Article] SCFSSTrcp mediates stress-induced Cdc25B ubiquitylation through cooperation of an atypical consensus sequence and PEST (2011)
  • Author(s): Uchida, S., Watanabe, N., Kudo, Y., et al
  • Journal Title: J Cell Sci Volume: 124 Pages: 2816-2825
  • Peer Reviewed
• [Journal Article] miR-22 represses cancer progression by inducing cellular senescence (2011)
  • Author(s): Xu, D., Takeshita, F., Hino, Y., Fukunaga, S., Kudo, Y., et al
  • Journal Title: J Cell Biol Volume: 193 Pages: 409-424
  • Peer Reviewed
• [Presentation] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis (2013)
  • Author(s): Kudo Y, Tsunematsu T, Ishimaru N
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
• [Presentation] Chromosome passenger complex protein Borealin is regulated by APC/C^<Cdh>1 ubiquitin ligase complex (2013)
  • Author(s): Tsunematsu T, Kudo Y
  • Organizer: 第35回内藤カンファレンス
  • Place of Presentation: シャトレーゼガトーキングダム札幌(北海道札幌市)
• [Presentation] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis (2013)
  • Author(s): K udo Y, Tsunematsu T, Ishimaru N
  • Organizer: 第35回内藤カンファレンス
  • Place of Presentation: シャトレーゼガトーキングダム札幌(北海道札幌市)
• [Presentation] Chromosome passenger complex protein,Borealin is regulated by APC/CCdh1 ubiquitin ligase complex, (2013)
  • Author(s): Tsunematsu Takaaki and Yasusei Kudo
  • Organizer: 第35回Naito Conference
  • Place of Presentation: シャトレーゼ ガトーキングダム札幌（北海道札幌市）
• [Presentation] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis (2013)
  • Author(s): Yasusei Kudo, Tsunematsu Takaaki and Naozumi Ishimaru
  • Organizer: 第35回Naito Conference,
  • Place of Presentation: シャトレーゼ ガトーキングダム札幌（北海道札幌市）
• [Presentation] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and CDT1 in mitosis (2013)
  • Author(s): Yasusei Kudo, Tsunematsu Takaaki and Naozumi Ishimaru
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
• [Presentation] 分裂期キナーゼAurora-AによるDNAライセンス化抑制因子Gemininの安定化機構 (2012)
  • Author(s): 常松貴明,工藤保誠,高田隆
  • Organizer: 第23回日本臨床口腔病理学会・学術大会
  • Place of Presentation: 東京医科歯科大学(東京都)
  • Year and Date: 2012-08-30
• [Presentation] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis (2012)
  • Author(s): Kudo Y, Tsunematsu T, Takata T
  • Organizer: Cold Spring Harbor Meeting,"The Cell Cycle"
  • Place of Presentation: コールドスプリングハーバー研究所(ニューヨーク, USA)
  • Year and Date: 2012-05-16
• [Presentation] 細胞分裂期キナーゼAurora-AによるDNA複製調節機構 (2012)
  • Author(s): 常松貴明,工藤保誠,高田隆
  • Organizer: 第101回日本病理学会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2012-04-28
• [Presentation] 分裂期においてGemininはAurora-Aによるリン酸化によってユビキチン分解を免れる (2012)
  • Author(s): 常松貴明,工藤保誠,高田隆
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌(北海道札幌市)
• [Presentation] 分裂期において染色体パッセンジャータンパクであるBorealinは,APC/C^<Cdh>1ユビキチンリガーゼ複合体により制御される (2012)
  • Author(s): 工藤保誠,常松貴明,近藤智之,石丸直澄,高田隆
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌(北海道札幌市)
• [Presentation] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin and Cdt1 in mitosis. (2012)
  • Author(s): Kudo Y
  • Organizer: Cold Spring Harbor Meeting, The Cell Cycle
  • Place of Presentation: Cold Spring Harbor, New York
• [Presentation] 分裂期においてGemininはAurora-Aによるリン酸化によってユビキチン分解を免れる (2012)
  • Author(s): 常松 貴明
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌（北海道）
• [Presentation] 染色体パッセンジャータンパクであるBorealinは，APC/C-Cdh1ユビキチンリガーゼ複合体により制御される (2012)
  • Author(s): 工藤 保誠
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌（北海道）
• [Presentation] 分裂期キナーゼAurora-AによるDNAライセンス化抑制因子Gemininの安定化機構 (2012)
  • Author(s): 常松貴明
  • Organizer: 第23回日本臨床口腔病理学会・学術大会
  • Place of Presentation: 東京医科歯科大学（東京都）
• [Presentation] 細胞分裂期キナーゼAurora-AによるDNA複製調節機構 (2012)
  • Author(s): 常松貴明
  • Organizer: 第101回日本病理学会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] Identification of novel invasion related molecules in oral cancer (2011)
  • Author(s): 工藤保誠
  • Organizer: 第5回アジア口腔病理学会・第22回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 九州大学医学部(福岡県福岡市)
  • Year and Date: 2011-08-24
  • Invited
• [Presentation] Identification of novel invasion related molecules in oral cancer (2011)
  • Author(s): 工藤保誠
  • Organizer: 第5回アジア口腔病理学会・第22回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 福岡市(九州大学医学部)(招待講演)
  • Year and Date: 2011-08-24
• [Presentation] Geminin stabilization by Aurora kinase-mediated phosphorylation during mitosis (2011)
  • Author(s): Tsunematsu T, Kudo Y, Takata T
  • Organizer: Cold spring harbor Meeting"The ubiquitin family"
  • Place of Presentation: コールドスプリングハーバー研究所(ニューヨーク, USA)
• [Presentation] Chromosome passenger complex protein, Borealin is regulated by APC/C^<Cdh>1 ubiquitin ligase complex (2011)
  • Author(s): Kudo Y, Tsunematsu T, Takata T
  • Organizer: Cold spring harbor Meeting"The ubiquitin family"
  • Place of Presentation: コールドスプリングハーバー研究所(ニューヨーク, USA)
• [Presentation] Geminin stabilization by Aurora kinase-mediated phosphorylation during mitosis (2011)
  • Author(s): Tsunematsu T, Kudo Y, Takata T
  • Organizer: Cold spring harbor meeting "The ubiquitin family"
  • Place of Presentation: ニューヨーク,アメリカ合衆国
• [Presentation] Chromosome passenger complex protein, Borealin is regulated by APC/C^<Cdhl> ubiquitin ligase complex (2011)
  • Author(s): Kudo Y, Tsunematsu T, Takata T
  • Organizer: Cold spring harbor meeting "The ubiquitin family"
  • Place of Presentation: ニューヨーク,アメリカ合衆国