Cell cycle regulation via ubiquitin system

2011 Fiscal Year Final Research Report

• Project Area: Cell Proliferation Control
• Project/Area Number: 19057005
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: KITAGAWA Masatoshi 浜松医科大学, 医学部, 教授 (50294971)
• Co-Investigator(Kenkyū-buntansha): WATANABE Nobumoto 独立行政法人理化学研究所, 化合物バンク評価研究チーム, チームヘッド (90221689)
• Project Period (FY): 2007 – 2011
• Keywords: ユビキチン / リン酸化 / タンパク分解 / 細胞周期

Research Abstract

In this research, we investigated regulation of both cell cycle regulators and differentiation factors via post-translational modification such as ubiquitylation and phospholylation to solve the molecular mechanisms of cell cycle and cell differentiation and thereby We aim at the contribution to the cause elucidation and cure for human disease development of symptoms. We achieved the following success in this research. (1)Phosphorylation-dependent degradation of c-Myb. (2) Inhibition of SCF-Fbw7 by adenovirus E1A protein. (3) Pirh2 as a novel E3 ligase for p27. (4) Involvement of Skp2/p27 axis in nephropathy (5) Regulation of Mig-6 by Chk1. (6)Regulation of Wee1 via CK2 and Plk (7) Identification of binding inhibitor of polobox domain to .-TrCP (8) JNK function in .-TrCP-mediated ubiquitylation of Cdc25B

Research Products

• [Journal Article] Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome (2012)
  • Author(s): Egawa, K., Kitagawa, K., Inoue K., Takayama, M., Takayama, C., Saitoh, S., Kishino, T., Kitagawa, M., Fukuda, A
  • Journal Title: Sci Transl Med Volume: 4, 163ra157 Pages: 1-10
• [Journal Article] Chk1 phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling (2012)
  • Author(s): Liu, N., Matsumoto M., Kitagawa K., Kotake Y., Suzuki S., Shirasawa S., Nakayama KI., Nakanishi M., Niida H., Kitagawa M
  • Journal Title: EMBO J Volume: 31 Pages: 2365-2377
  • Peer Reviewed
• [Journal Article] Long noncoding RNA involved in cancer development and cell fate determination (2012)
  • Author(s): Kitagawa, M., Kotake, Y. and Ohhata, T
  • Journal Title: Curr. Drug Targets Volume: 13 Pages: 1616-1621
• [Journal Article] The SCF ubiquitin ligases involved in hematopoietic linage (2012)
  • Author(s): Kitagawa, K. and Kitagawa, M
  • Journal Title: Curr. Drug Targets Volume: 13 Pages: 1641-1648
  • Peer Reviewed
• [Journal Article] Regulation of DNA replication licensing (2012)
  • Author(s): Niida, H. and Kitagawa, M
  • Journal Title: Curr. Drug Target Volume: 13 Pages: 1588-1592
  • Peer Reviewed
• [Journal Article] Phosphorylation-dependent protein-protein interaction modules as potential molecular targets for cancer therapy Curr (2012)
  • Author(s): Watanabe, N. and Osada H
  • Journal Title: Drug Targets Volume: 13 Pages: 1654-1658
  • Peer Reviewed
• [Journal Article] The amelioration of renal damage in Skp2-deficient mice is canceled by p27^<Kip1> deficiency in Skp^<2-/>- p27^<-/-> mice (2012)
  • Author(s): Suzuki, S., Fukasawa, H., Misaki, T., Togawa A., Ohashi, N., Kitagawa, K., Kotake, Y., Niida, H., Liu, N., Nakayama. K., Nakayama, K.I., Yamamoto, T. and Kitagawa, M
  • Journal Title: PLoS ONE Volume: 7 Pages: e31249
  • Peer Reviewed
• [Journal Article] Protein Degradation by the Ubiquitin-Proteasome Pathway and Organ Fibrosis (2012)
  • Author(s): Fukasawa, H., Fujigaki Y., Yamamato, T., Hishida, A. and Kitagawa, M
  • Journal Title: Current Medicinal Chemistry (review article) Volume: 19 Pages: 893-900
  • Peer Reviewed
• [Journal Article] Up-regulation of Cks1 and Skp2 with TNFa/NFkB signaling in chronic progressive nephropathy (2011)
  • Author(s): Suzuki, S., Fukasawa, H., Misaki, T., Togawa A., Ohashi, N., Kitagawa, K., Kotake, Y., Niida, H., Hishida, A., Yamamoto, T. and Kitagawa M
  • Journal Title: Genes Cells Volume: 16 Pages: 1110-1120
• [Journal Article] Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene (2011)
  • Author(s): Kotake, Y., Nakagawa, T., Kitagawa, K., Suzuki, S., Liu, N., Kitagawa, M. and Xiong, Y. (co-corresponding authors)
  • Journal Title: Oncogene Volume: 30 Pages: 1956-1962
• [Journal Article] Coordinated regulation of differentiation and proliferation of embryonic cardiomyocytes by a Jumonnji (Jarid2)-cyclin D1 pathway (2011)
  • Author(s): Nakajima, K., Inagawa, M., Uchida, C., Okada, K., Kojima, M., Kubota, K., Noda, M., Ogawa S., Shirato, H., Sato M., Suzuki-Migishima, R., Hino, T., Kitagawa, M. and Takeuchi, T
  • Journal Title: Development Volume: 138 Pages: 1771-1782
• [Journal Article] Morphobase, an encyclopedic cell morphology database, and its use for drug target identification (2011)
  • Author(s): Futamura, Y. Kawatani, M., Kazami, S., Tanaka, K., Muroi, M., Shimizu, T., Tomita, K., Watanabe, N., Osada, H
  • Journal Title: Chem Biol Volume: 19 Pages: 1620-1630
• [Journal Article] Vipirinin, a coumarin-based HIV-1 VPR inhibitor, interacts with a hydrophobic region of VPR (2011)
  • Author(s): Ong, EB., Watanabe, N., Saito, A., Futamura, Y., Abd El Galil, K.H., Koito, A., Najimudin, N., Osada, H
  • Journal Title: J Biol. Chem Volume: 286 Pages: 14049-14056
• [Journal Article] SCFβTrCP mediates stress-activated MAP kinase-induced Cdc25B degradation (2011)
  • Author(s): Uchida, S., Watanabe, N., Kudo, Y., Yoshioka, K., Matsunaga, T., Ishizaka, Y., Nakagama, H., Poon, R.Y.C., and Yamashita, K
  • Journal Title: J. Cell Sci Volume: 124 Pages: 2816-2825
• [Journal Article] GSK3 regulates the expression of human and mouse c-Myb via different mechanisms (2010)
  • Author(s): Kitagawa, K., Kotake, Y., Hiramatsu, Y., Liu, N., Suzuki, S., Nakamura, S., Kikuchi, A. and Kitagawa, M
  • Journal Title: Cell Div Volume: 5 Pages: 27
• [Journal Article] Kaposi's sarcoma-associated herpesvirus- encoded LANA positively affects on ubiquitylation of p53 (2010)
  • Author(s): Suzuki, T., Isobe, T., Kitagawa, M. and Ueda, K
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 403 Pages: 194-197
• [Journal Article] Mellman, I. and Cantley, L.G.: Hepatocyte Growth Factor stimulated cell scattering requires ERK and Cdc42-dependent Tight Junction Disassembly (2010)
  • Author(s): Togawa, A., Sfakianos, J., Ishibe, S., Suzuki, S., Fujigaki, Y., Kitagawa, M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 400 Pages: 271-277
• [Journal Article] Dual mode of regulation of Cdc25A protein by TRB3 (2010)
  • Author(s): Sakai, S., Ohoka, N., Onozaki, K., Kitagawa, M., Nakanishi, M. and Hayashi, H
  • Journal Title: Biol. Pharm. Bull Volume: 33 Pages: 1112-1116
• [Journal Article] Reduction of transforming growth factor-s type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma (2010)
  • Author(s): Fukasawa, H., Yamamoto, T., Fujigaki, Y., Misaki, T., Ohashi, N., Takayama, T., Suzuki, S., Mugiya, S., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Hayashi, H., Ozono, S., Kitagawa, M. and Hishida, A
  • Journal Title: Int. J. Cancer Volume: 127 Pages: 1517-1525
• [Journal Article] p27 modulates tropism of mesenchymal stem cells toward brain tumors (2010)
  • Author(s): Gao, Y., Gu, C., Li, S., Tokuyama, T., Yokota, N., Nakayama, K.I., Kitagawa, M. and Namba, H
  • Journal Title: Exp. Ther. Med Volume: 1 Pages: 695-699
• [Journal Article] Mapping of the interaction sites between Weel kinase and the regulatory b-subunit of protein kinase CK2 (2010)
  • Author(s): Olsen, BB., Kreutzer, N., Watanabe, N., Holm, T. and Guerra, B
  • Journal Title: Int. J. Oncol Volume: 36 Pages: 1175-1182
• [Journal Article] Adenovirus E1A inhibits SCFFbw7 ubiquitin ligase (2009)
  • Author(s): Isobe, T., Hattori, T., Kitagawa, K., Uchida, C., Kotake, Y., Kosugi, I., Oda, T. and Kitagawa, M
  • Journal Title: J. Biol. Chem Volume: 284 Pages: 27766-27779
• [Journal Article] Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb (2009)
  • Author(s): Kitagawa, K., Hiramatsu, Y., Uchida, C., Isobe, T., Hattori, T., Oda, T., Shibata, K., Nakamura, S., Kikuchi, A. and Kitagawa, M
  • Journal Title: Oncogene Volume: 28 Pages: 2383-2405
• [Journal Article] Ubiquitin-mediated control of oncogene and tumor suppressor gene products (2009)
  • Author(s): Kitagawa, K., Kotake, Y. and Kitagawa, M
  • Journal Title: Cancer Sci Volume: 100 Pages: 1374-1381
• [Journal Article] Decrease in TRADD resulted from ubiquitin-dependent degradation in the obstructive renal injury in rats (2009)
  • Author(s): Misaki, T., Yamamoto, T., Suzuki, S., Fukasawa, H., Togawa, A., Ohashi, N., Suzuki, H., Fujigaki, Y., Oda, T, Uchida, C., Kitagawa, K., Hattori, T., Kitagawa, M. and Hishida, A
  • Journal Title: Am. J. Pathol Volume: 175 Pages: 74-83
• [Journal Article] High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers (2009)
  • Author(s): Shimada, M., Kitagawa, K., Dobashi, Y., Isobe, T., Hattori, T., Uchida, C., Abe, K., Kotake, Y., Oda, T., Suzuki, H., Hashimoto, K. and Kitagawa, M
  • Journal Title: Cancer Sci Volume: 100 Pages: 866-872
• [Journal Article] Polo-like kinase 1 phosphorylates and regulates Bcl-xL during pironetin-induced apoptosis (2009)
  • Author(s): Tamura, Y., Simizu, S., Muroi, M., Takagi, S., Kawatani, M., Watanabe, N., and Osada, H
  • Journal Title: Oncogene Volume: 28 Pages: 107-116
• [Journal Article] Deficiency in chromosome congression by the inhibition of PLK1 polo box domain-dependent recognition (2009)
  • Author(s): Watanabe, N., Sekine, T., Takagi, M., Iwasaki, J., Imamoto, N., Kawasaki, H., and Osada, H
  • Journal Title: J Biol. Chem Volume: 284 Pages: 2344-2353
• [Journal Article] TSU68 prevents liver metastasis of colon cancer xenografts by modulating the pre-metastatic niche (2008)
  • Author(s): Yamamoto, M., Kikuchi, H., Ohta, M., Kawabata, T., Hiramatsu, Y., Kondo, K., Baba, M,. Kamiya, K., Tanaka, T., Kitagawa M. and Konno, H
  • Journal Title: Cancer Res Volume: 68 Pages: 9754-9762
• [Journal Article] Intrarenal RAS activity and urinary angiotensinogen excretion in anti-thymocyte serum nephritis rats (2008)
  • Author(s): Ohashi, N., Yamamoto, T., Huang, Y., Misaki, T., Fukasawa, H., Suzuki, H., Togawa, A., Suzuki, S., Fujigaki, Y., Nakagawa, T., Nakamura, Y., Suzuki, F., Kitagawa, M. and Hishida, A
  • Journal Title: Am. J. Physiol Renal Physiol Volume: 295 Pages: F1512-1518
• [Journal Article] Novel insights into FGD3, a putative GEF for Cdc42, that undergoes SCF/b-TrCP-mediated proteasomal degradation analogous to that of its homologue FGD1 but regulates cell morphology and motility differently from FGD1 (2008)
  • Author(s): Hayakawa, M., Matsushima, M., Hagiwara, H., Oshima, T., Fujino, T., Ando, K., Kikugawa, K., Tanaka, H., Miyazawa,K. and Kitagawa, M
  • Journal Title: Genes to Cells Volume: 13 Pages: 329-442
• [Journal Article] Pirh2 interacts with and ubiquitylates signal recognition particle receptor beta subunit (2008)
  • Author(s): Abe, K., Hattori, T., Isobe, T., Kitagawa, K., Oda, T., Uchida, C., and Kitagawa, M
  • Journal Title: Biomed Res Volume: 29 Pages: 53-60
• [Journal Article] Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells (2008)
  • Author(s): Kurata, K., Yanagisawa, R., Ohira, M., Kitagawa, M., Nakagawara, A. and Kamijo, T
  • Journal Title: Oncogene Volume: 27 Pages: 741-754
• [Journal Article] Regulation of TGF-beta signaling by Smads and its roles in tissue fibrosis (2008)
  • Author(s): Fukasawa, H., Yamamato, T., Kitagawa, M. and Hishida, A
  • Journal Title: Current signal transduction therapy (review article) Volume: 3 Pages: 1-6
• [Journal Article] Human immunodeficiency virus type 1 Vpr binds to the N lobe of the Wee1 kinase domain and enhances kinase activity for CDC2 (2008)
  • Author(s): Kamata, M., Watanabe, N., Nagaoka, Y., and Chen, IS
  • Journal Title: J Virol Volume: 82 Pages: 5672-5682
• [Journal Article] The regulatory b-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis (2008)
  • Author(s): Yde, C.W., Olsen, B.B., Meek, D., Watanabe, N., and Guerra, B
  • Journal Title: Oncogene Volume: 27 Pages: 4986-4997
• [Journal Article] Pirh2 Promotes Ubiquitin-Dependent Degradation of the CDK Inhibitor p27Kip1 (2007)
  • Author(s): Hattori, T., Isobe, T., Abe, K., Kikuchi, H., Kitagawa, K., Oda, T., Uchida, C. and Kitagawa, M
  • Journal Title: Cancer Res Volume: 67 Pages: 10789-10795
• [Journal Article] Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion (2007)
  • Author(s): Ohoka, N., Hattori, T., Kitagawa, M., Onozaki, K. and Hayashi H
  • Journal Title: J. Biol. Chem Volume: 282 Pages: 35687-35694
• [Journal Article] Contribution of Extracellular Signal-Regulated Kinases to the IL-1-induced Growth Inhibition of Human Melanoma Cells A375 (2007)
  • Author(s): Arakawa, T., Yamamura, T., Hattori, T., Hayashi H., Mori, A., Yoshida, A., Uchida, C., Kitagawa, M. and Onozaki, K
  • Journal Title: Int. Immunopharm Volume: 8 Pages: 80-89
• [Journal Article] Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia (2007)
  • Author(s): Kono, S., Suzuki, H., Oda, T., Takahashi, Y., Shirakawa, K., Takahashi, Y., Kitagawa, M. and Miyajima, H
  • Journal Title: J. Hepatology Volume: 47 Pages: 844-850
• [Journal Article] Effect of loss of heterozygosity of the c-kit gene on prognosis after hepatectomy for metastatic liver gastrointestinal stromal tumors (2007)
  • Author(s): Kikuchi, H., Yamamoto, M., Hiramatsu, Y., Baba, M., Ohta, M., Kamiya, K., Tanaka, T., Suzuki, S., Sugimura, H., Kitagawa, M., Kanai, T., Kitayama, Y., Kanda, T., Nishikura, K. and Konno, H
  • Journal Title: Cancer Sci Volume: 98 Pages: 1734-1739
• [Journal Article] ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells (2007)
  • Author(s): Kikuchi, H., Uchida, C., Hattori, T., Isobe, T., Hiramatsu, Y., Kitagawa, K., Oda, T., Konno, H. and Kitagawa, M
  • Journal Title: Carcinogenesis Volume: 28 Pages: 1752-1758
• [Journal Article] Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice (2007)
  • Author(s): Suzuki, S., Fukasawa, H., Kitagawa, K., Uchida, C., Hattori, T., Isobe, T., Oda, T., Misaki, T., Ohashi, N., Nakayama, K., Nakayama, K.I., Hishida, A., Yamamoto, T. and Kitagawa, M
  • Journal Title: Am. J. Pathol Volume: 171 Pages: 473-483
• [Journal Article] Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage (2007)
  • Author(s): Inoue, Y., Kitagawa, M. and Taya, Y
  • Journal Title: EMBO J Volume: 26 Pages: 2083-2093
• [Journal Article] Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites (2007)
  • Author(s): Li, S., Gao, Y., Tokuyama, T., Yamamoto, J., Yokota, N., Yamamoto, S., Terakawa, S., Kitagawa, M. and Namba, H
  • Journal Title: Cancer Lett Volume: 251 Pages: 220-227
• [Journal Article] Roles of the Skp2/p27 axis in the progression of chronic nephropathy
  • Author(s): Suzuki, S., Ohashi, N. and Kitagawa, M
  • Journal Title: Cell Mol Life Sci Volume: (in press)
  • DOI: 10.1007/s00018-012-1232-x
• [Presentation] Chk1 phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling (2012)
  • Author(s): 北川雅敏、劉寧
  • Organizer: 第45回日本発生生物学会、第64回日本細胞生物学会合同年会
  • Place of Presentation: 神戸
  • Year and Date: 2012-05-31
• [Presentation] Phosphorylation-mediated regulation of the tumor suppressor Mig-6 (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Chk1の新機能 (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-22
• [Presentation] 長鎖ノンコーディングRNA ANRILは INK4 locusの転写抑制を介し細胞増殖に関与する (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本細胞生物学会
  • Place of Presentation: 札幌
  • Year and Date: 2011-06-27
• [Presentation] Role of phosphorylation dependent protein-protein interaction on the cell cycle progression (2010)
  • Author(s): Watanabe, N
  • Organizer: MEXT Priority Research Project "Cell Proliferation Control" International Symposium Cell Cycle and Cell Differentiation From A to Z
  • Place of Presentation: 名古屋
  • Year and Date: 20101100
• [Presentation] A small molecule inhibitor of phosphorylation-dependent protein-protein interaction (2010)
  • Author(s): Watanabe, N. et al.
  • Organizer: 8th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Place of Presentation: ハワイ州、ワイコロア
  • Year and Date: 2010-02-09
• [Presentation] アデノウイルスE1A蛋白質はSCF-Fbw7ユビキチンリガーゼを阻害する (2009)
  • Author(s): 北川雅敏、磯部智康
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-12
• [Presentation] Role of peptidyl prolyl isomerization during M-phase progression (2009)
  • Author(s): 渡邉信元 他
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-12
• [Presentation] Screening of small molecule inhibitors for polo box domain dependent interaction (2009)
  • Author(s): 渡邉信元 他
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] Pirh2はp27のユビキチンリガーゼとしてヒトの癌の悪性化に関与する (2009)
  • Author(s): 北川雅敏 他
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] 小分子阻害剤を用いた細胞分裂におけるPBD依存性結合の役割の解析 (2008)
  • Author(s): 渡邉信元 他
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会 (BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] 細胞周期制御分子p27のユビキチン依存的分解機構と病態 (2007)
  • Author(s): 北川雅敏
  • Organizer: 第30回日本分子生物学会第, 80回日本生化学会合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-12
• [Presentation] Novel regulatory mechanisms of Cyclin D1 expression (2007)
  • Author(s): Kitagawa, M. et al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] 癌関連核内因子のユビキチン依存的制御機構 (2007)
  • Author(s): 北川雅敏
  • Organizer: Nuclear Signaling JAPAN 2007シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-07-13
• [Book] 癌細胞の細胞周期異常日本臨牀, 67巻増刊号1 「癌薬物療法学 基礎・臨床研究のアップデート」 (2009)
  • Author(s): 渡邉信元 他
• [Book] がん化学療法・分子標的治療 update (西條長広、西尾和人 編) 第2章 がん化学療法の標的 3. 細胞周期 (2009)
  • Author(s): 渡邉信元 他
  • Publisher: 中外医学社
• [Remarks]
  • URL: http://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html
• [Patent(Industrial Property Rights)] 癌治療用組成物 (2012)
  • Inventor(s): 北川雅敏、高芸、北川恭子
  • Industrial Property Rights Holder: 浜松医科大学
  • Industrial Property Number: 特許、4967137
  • Filing Date: 2012-02-16
• [Patent(Industrial Property Rights)] 癌の転移性及び浸潤能の検査方法 (2011)
  • Inventor(s): 北川雅敏、高芸、北川恭子
  • Industrial Property Rights Holder: 浜松医科大学
  • Industrial Property Number: 特許、4887505
  • Filing Date: 2011-12-22