Mechanisms for the regulation of growth and cell death in cancer cells

2009 Fiscal Year Final Research Report

• Project/Area Number: 17014043
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: KAKIZUKA Akira Kyoto University, 大学院・生命科学研究科, 教授 (80204329)
• Project Period (FY): 2005 – 2009
• Keywords: 細胞死 / AAA / ATPase / アミノ酸修飾

Research Abstract

In order to build fundamentals for developing novel cancer treatment, we have analyzed the functions of VCP (an ATPase), which is involved in cell growth and cell death. Resultantly, we identified VCP being modified at many amino acid residues, by which VCP is involved in the cellular functions such as controls of cell cycle and reactive oxygen species. In most of examined advanced adeno-carcinomas and squamous cell carcinomas, we observed highly elevated expression of VCP and p47, a VCP co-factor, suggesting their involvement in the invasion and metastasis.

Research Products

• [Journal Article] Enhanced ATPase activities as a primary defect of mutant valosin-containing proteins (VCPs) that cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). (2010)
  • Author(s): Manno, A., Noguchi, M., Fukushi, J., Motohashi, Y., Kakizuka, A.
  • Journal Title: Genes Cells (in press)
• [Journal Article] Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression. (2010)
  • Author(s): Koike M, Fukushi J, Ichinohe Y, Higashimae N, Fujishiro M, Sasaki C, Yamaguchi M, Uchihara T, Yagishita S, Ohizumi H, Hori S, Kakizuka A.
  • Journal Title: J Biol Chem. (In press)
• [Journal Article] Maintaining ATP levels via the suppression of PERK-mediated rRNA synthesis at ER stress. (2010)
  • Author(s): Okamoto, A., Koike, M., Yasuda, K., Kakizuka A.
  • Journal Title: Biochem. Biophys. Res. Commun. Pages: 42-47
• [Journal Article] Glucosamine induces autophagy via an mTOR-independent pathway. (2010)
  • Author(s): Shintani, T., Yamazaki, F., Katoh, T., Umekawa, M., Matahira, Y., Hori, S., Kakizuka, A., Totani, K., Yamamoto, K., Ashida, H.
  • Journal Title: Biochem. Biophys. Res. Commun. 391 Pages: 1775-1779
• [Journal Article] Listeria monocytogenes ActA-mediated escape from autophagic recognition. (2009)
  • Author(s): Yoshikawa, Y., Ogawa, M., Hain T., Yoshida, M., Fukumatsu, M., Kim, M., Mimuro, H., Nakagawa, I., Yanagawa, T., Ishii, T., Kakizuka, A., Sztul, E., Chakraborty, T., Sasakawa, C.
  • Journal Title: Nat Cell Biol. Pages: 1233-1240
• [Journal Article] p97/valosine- containing protein (VCP) is highly modulated by phosphorylation and acetylation. (2009)
  • Author(s): Mori-Konya, C., Kato, N., Maeda, R., Yasuda, K., Higashimae, N., Noguchi, M., Koike, M., Kimura, Y., Ohizumi, H., Hori, S., Kakizuka, A.
  • Journal Title: Genes Cells 14 Pages: 483-497
• [Journal Article] An inhibitor of a deubiquitingating enzyme regulates ubiquitin homeostasis. (2009)
  • Author(s): Kimura Y, Yashiroda H, Kudo T, Koitabashi S, Murata S, Kakizuka A, Tanaka K.
  • Journal Title: Cell 137 Pages: 549-559
• [Journal Article] Roles of VCP in human neurodegenerative disorders. (2008)
  • Author(s): Kakizuka A.
  • Journal Title: Biochem. Soc. Trans. 36 Pages: 105-10
• [Journal Article] Direct detection of the interaction between recombinant soluble extracellular regions in the heterodimeric metabotropic gamma- aminobutyric acid receptor. (2008)
  • Author(s): Nomura, R., Suzuki, Y., Kakizuka, A., Jingami, H.
  • Journal Title: J Biol Chem. 283 Pages: 4665-4673
• [Journal Article] Involvement of valosin-containing protein (VCP)/p97 in the formation and clearance of abnormal protein aggregates. (2007)
  • Author(s): Kobayashi, T., Manno, A., Kakizuka, A.
  • Journal Title: Genes Cells. 12 Pages: 889-901
• [Journal Article] In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR alpha blockade in the pathogenesis of acute promyelocytic leukemia. (2006)
  • Author(s): Matsushita, H., Scaglioni, P.P., Bhaumik, M., Rego, E.M., Cai, L. F, Majid, S.M., Miyachi, H., Kakizuka, A., Miller, W.H. Jr., Pandolfi, P.P.
  • Journal Title: J Exp Med. 203 Pages: 821-828
• [Journal Article] Dominant-negative effect of mutant valosin-containing protein in aggresome formation. (2006)
  • Author(s): Kitami, M.I., Kitami, T., Nagahama, M., Tagaya, M., Hori, S., Kakizuka, A., Mizuno, Y., Hattori, N.
  • Journal Title: FEBS Lett. 580 Pages: 474-478
• [Journal Article] Induction of murine leukemia and lymphoma by dominant negative retinoic acid receptor alpha. (2005)
  • Author(s): Wang, Y.A., Shen, K., Ishida, Y., Wang, Y., Kakizuka, A., Brooks, S.C.
  • Journal Title: Mol Carcinog. 44 Pages: 252-261
• [Journal Article] ATPase activity of Valosin-containing protein (VCP) is regulated by oxidative modification of the evolutionally conserved 522nd cysteine residue in Walker A motif. (2005)
  • Author(s): Noguchi, M., Takata, T. Kimura, Y., Manno, A., Murakami, K., Koike, M., Ohizumi, H., Hori, S., Kakizuka A.
  • Journal Title: J. Biol. Chem. 280 Pages: 41332-41341
• [Journal Article] Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-x(L). (2005)
  • Author(s): Chou, A.H., Yeh, T.H., Kuo, Y.L., Kao, Y.C., Jou, M.J., Hsu, C, Y., Tsai, S.R., Kakizuka, A., Wang, H.L.
  • Journal Title: Neurobiol Dis. 21 Pages: 333-345
• [Journal Article] Retinoid signaling competence and RARbeta-mediated gene regulation in the developing mammalian telencephalon. (2005)
  • Author(s): Liao, W.L., Wang, H.F., Tsai, H.C., Chambon, P., Wagner, M., Kakizuka, A., Liu, F.C.
  • Journal Title: Dev. Dyn. 232 Pages: 887-900
• [Journal Article] - alpha, beta -unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor gamma. (2005)
  • Author(s): Shiraki, T., Kamiya, N., Shiki, S., Kodama, T.S., Kakizuka, A., Jingami, H.
  • Journal Title: J. Biol. Chem. 279 Pages: 51376-51385
• [Presentation] ストレス応答におけるVCP蛋白質の役割, ストレス応答の新機軸 (2009)
  • Author(s): 垣塚彰
  • Organizer: 第82回日本生化学会シンポジウム
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2009-10-24
• [Presentation] 細胞機能におけるVCP蛋白質の役割 (2009)
  • Author(s): 垣塚彰
  • Organizer: 第10回京都大学生命科学研究科シンポジウム
  • Place of Presentation: 芝蘭会館
  • Year and Date: 2009-07-02
• [Presentation] A novel feedback machinery between abnormal protein accumulation and transcriptional suppression. (2009)
  • Author(s): Akira Kakizuka
  • Organizer: The 5th NTU-Kyoto-U mini-symposium on molecular and cellular biology.
  • Place of Presentation: Raku-yu Kaikan, Kyoto, Japan.
  • Year and Date: 2009-05-23
• [Presentation] 癌ってどうゆうもの? (2009)
  • Author(s): 垣塚彰
  • Organizer: 膳所高等学校・京都大学公開講義
  • Place of Presentation: 京都大学
  • Year and Date: 2009-05-08
• [Presentation] 異常蛋白質の蓄積がもたらすフィードバック機構 (2008)
  • Author(s): 垣塚彰
  • Organizer: 第9回京都大学生命科学研究科シンポジウム
  • Place of Presentation: 京大会館
  • Year and Date: 2008-06-26
• [Presentation] 分子が織りなす生命の不思議-どうして病気になるの? 運動しても肥満は防げない? がん・神経難病、肥満・糖尿病をめぐって- (2008)
  • Author(s): 垣塚彰
  • Organizer: 徳島県立総合大学校まなーびあ徳島開校記念講演
  • Place of Presentation: 徳島県立総合教育センター(徳島県板野郡)
  • Year and Date: 2008-06-08
• [Presentation] Roles of VCP in human neurodegenerative disorders (2007)
  • Author(s): Akira Kakizuka
  • Organizer: 7th international conference on AAA proteins.
  • Place of Presentation: Royal Agricultural College, Cirencester (England)
  • Year and Date: 2007-09-11
• [Presentation] 「癌ってどういうもの?」文部科学省科学研究費補助金特定領域研究「がん特定」公開シンポジウム 「高校生の諸君に伝えたい、がん研究の今!」 (2006)
  • Author(s): 垣塚彰
  • Organizer: 第3回出前授業
  • Place of Presentation: 徳島県立城南高等学校
  • Year and Date: 2006-11-20
• [Presentation] VCP蛋白質の機能解析, 細胞死研究の新たな展開と関連する素過程 (2006)
  • Author(s): 垣塚彰
  • Organizer: 平成18年度生理学研究所研究会
  • Place of Presentation: 生理学研究所
  • Year and Date: 2006-10-31
• [Presentation] 細胞周期におけるVCP蛋白質の機能解析 (2005)
  • Author(s): 垣塚彰
  • Organizer: 第78回日本生化学会大会ランチョンセミナー
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2005-10-20
• [Presentation] ATPase activity of Valosin-containing protein (VCP) is regulated by oxidative modification of the evolutionally conserved 522nd cysteine residue in Walker A motif (2005)
  • Author(s): Akira Kakizuka
  • Organizer: 6th international conference on AAA proteins.
  • Place of Presentation: Schloss Seggau, Austria
  • Year and Date: 2005-09-15
• [Book] ヒトの分子生物学(分子生物学第2版(編集:柳田光弘、西田栄介、野田亮)) (2009)
  • Author(s): 垣塚彰
  • Total Pages: 261-273
  • Publisher: 東京科学同人
• [Book] ポリグルタミン病(脳神経科学イラストレイテッド改訂第2版(編集:森寿、真鍋俊也、渡辺雅彦、岡野栄之、宮川剛)) (2006)
  • Author(s): 垣塚彰
  • Total Pages: 312-319
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.lif.kyoto-u.ac.jp/labs/funcbiol/
• [Patent(Industrial Property Rights)] ペルオキシゾーム増殖剤応答性受容体活性剤および組成物 (2008)
  • Inventor(s): 垣塚彰、大滝佳代、大泉宏、庭野吉己、別府史章、鈴木尚志
  • Industrial Property Rights Holder: 京都大学、(株)サニーヘルス
  • Industrial Property Number: 特許・特願2008-227635
  • Filing Date: 2008-09-04
• [Patent(Industrial Property Rights)] 蛋白質切断活性を有する細胞のスクリーニング方法 (2007)
  • Inventor(s): 垣塚彰、山本幸男
  • Industrial Property Rights Holder: JST
  • Industrial Property Number: 特許・特許第4033637号
  • Acquisition Date: 2007-11-02