Mechanism and treatment for the disease caused by the impairment of PKC signaling

• Project/Area Number: 19390064
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kobe University
• Principal Investigator: SAITO Naoaki Kobe University, 自然科学系先端融合研究環バイオシグナル研究センター, 教授 (60178499)
• Co-Investigator(Kenkyū-buntansha): SHIRAI Yasuhito 神戸大学, 自然科学系先端融合研究環バイオシグナル研究センター, 准教授 (60263399) ; UEYAMA Takehiko 神戸大学, 自然科学系先端融合研究環バイオシグナル研究センター, 講師 (80346254)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2008: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2007: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
• Keywords: プロテインキナーゼC / 精髄小脳変性症 / カルシウム / 神経変性 / 遺伝子変異 / 脊髄小脳変性症 / パーキンソン病

Research Abstract

脊髄小脳変性症14型の発症メカニズムとして、変異型PKCγには細胞膜に十分な時間存在する能力が欠如しTRPCチャネルをリン酸化することができないため細胞外からのCa^<2+> 流入を抑制する機構が働かないことを示した。この過剰なCa^<2+> 流入が神経細胞死が招くと推測された。また他の要因として初代培養プルキンエ細胞において変異型PKCγは凝集体の形成・樹状突起の伸展・シナプス形成異常を引き起こす事を示した。

Research Products

• [Journal Article] Kinase activity of the dgk gene product is involved 1 in the virulence of Streptococcus mutans Microbiology (2009)
  • Author(s): Shibata, Y., van der Ploeg, JR., Kozuki, T., Shirai, Y., Saito, N., Kawada, M., Takeshita, T., and Yamashita, Y.
  • Journal Title: 155 Pages: 557-565
  • Peer Reviewed
• [Journal Article] Mutant γPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells (2009)
  • Author(s): Seki, T. ; Shimahara ; T., Yamamoto ; K., Abe ; N., Amano, T. ; Adachi ; N., Takahashi, H. ; Kashiwagi, K. ; Saito, N., Sakai, N.
  • Journal Title: Neurobiology of Disease 33 Pages: 260-273
  • Peer Reviewed
• [Journal Article] Kinase activity of the dgk gene product is involved 1 in the virulence of streptococcus mutans (2009)
  • Author(s): Shibata, Y., 他
  • Journal Title: Microbiology 155 Pages: 557-565
  • Peer Reviewed
• [Journal Article] Mutant γPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells. (2009)
  • Author(s): Seki, T., 他
  • Journal Title: Neurobiology of Disease 33 Pages: 260-273
  • Peer Reviewed
• [Journal Article] Diacylglycerol kinase β accumulates on the perisynaptic site of medium spiny neurons in the striatum (2008)
  • Author(s): Hozumi,Y., Fukaya, M., Adachi, N., Saito, N., Otani, K., Kondo, K., Watanabe, M., and Goto, K.
  • Journal Title: Eur. J. Neurosci 28 Pages: 2409-2422
  • Peer Reviewed
• [Journal Article] Ca^<2+> oscillation induced by P2Y2 receptor activation and its regulation by a neuron-specific subtype of PKC (βPKC) (2008)
  • Author(s): Ashida, N., Ueyama, T., Rikitake, K., Shirai, Y. Eto, M., Kondoh, T., Kohmura, E., and Saito, N.
  • Journal Title: Neurosci. Lett 446 Pages: 123-128
  • Peer Reviewed
• [Journal Article] Metabotropic glutamate receptor subtype-1 is essential for in vivo growth of melanoma (2008)
  • Author(s): Ohtani, Y., Harada, T., Funasaka, Y., Nakao, K., Takahara, C., Abdel-Daim, M., Sakai, N., Saito, N., Nishigori, C. and Aiba, A.
  • Journal Title: Oncogene 27 Pages: 7162-7170
  • Peer Reviewed
• [Journal Article] Reactive oxygen species derived from NOX1/NADPH oxidase enhance inflammatory pain (2008)
  • Author(s): Ibi, M., Matsuno, K., Shiba, D., Katsuyama, M., Iwata, K., Kakehi, T., Nakagawa, T., Sango, K., Shirai, Y., Yokoyama, T., Kaneko, S., Saito N.,and Yabe-Nishimura, C.
  • Journal Title: J. Neurosci 28 Pages: 9486-9494
  • Peer Reviewed
• [Journal Article] Minireview : Protein kinase Cε-function in neurons (2008)
  • Author(s): Shirai, Y., Adachi, N. and Saito, N.
  • Journal Title: FEBS J 275 Pages: 3988-3994
  • Peer Reviewed
• [Journal Article] Enzymological analysis of mutant protein kinase Cγ causing spinocerebellar ataxia type 14 and its dysfunction in Ca^<2+> homeostasis (2008)
  • Author(s): Adachi, N., Kobayashi, T., Takahashi, H., Kawasaki, T., Shirai, Y., Ueyama, T., Matsuda, T., Seki, T., Sakai, N. and Saito N.
  • Journal Title: J. Biol. Chem 283 Pages: 19854-19863
  • Peer Reviewed
• [Journal Article] Identification of SF-1/Ad4BP gene expression modulators by large scale gain and loss of function studies (2008)
  • Author(s): Sakai, N., Terami, H., Suzuki, S., Haga, M.,Nomoto, K., Tsuchida, N., Morohashi, KI.,Saito, N., Asada, M., Hashimoto, M.,Harada, D., Asahara, H., Ishikawa, T.,Shimada, F., Sakurada, K.
  • Journal Title: J. Endocrinol 198 Pages: 489-497
  • Peer Reviewed
• [Journal Article] Sequential Binding of Cytosolic Phox Complex to Phagosomes through Regulated Adaptor Proteins : Evaluation Using the Novel Monomeric Kusabira-Green System and Live Imaging of Phagocytosis (2008)
  • Author(s): Ueyama, T., Kusakabe, T., Karasawa, S., Kawasaki, T., Shimizu, A., Son J-H, Shirai, Y., Leto, TL., Miyawaki, A., and Saito N.
  • Journal Title: J. Immunol 181 Pages: 629-40
  • Peer Reviewed
• [Journal Article] Lck-dependent tyrosine phosphorylation of DGK alpha regulates its membrane association in T cells (2008)
  • Author(s): Merino, E. Avila-Flores, A., Shirai, Y., Moraga, I., Saito, N. and Merida, I.
  • Journal Title: J. Immunol 180 Pages: 5805-5815
  • Peer Reviewed
• [Journal Article] Immunogold electron microscopic demonstration of distinct submembranous localization of the activated γPKC depending on the stimulation (2008)
  • Author(s): Oyasu, M., Fujimiya, M., Kashiwagi, K., Ohmori, S., Imaeda, H. and Saito, N.
  • Journal Title: J. Histochem. Cytochem 56 Pages: 253-265
  • Peer Reviewed
• [Journal Article] Synthesis Conformational Analysis, and Biological Evaluation of 1-Hexyl-indolactam-V10 as a Selective Activator for Novel Protein Kinase C Isozymes (2008)
  • Author(s): Yanagita, RC, Nakagawa, Y., Yamanaka, N., Kashiwagi, K., Saito, N. and Irie, K.
  • Journal Title: J. Med. Chem 51 Pages: 46-56
  • Peer Reviewed
• [Journal Article] Regulation of Clathrin Dependent Endocytosis by Diacylglycerol kinaseδ (2008)
  • Author(s): Kawasaki, T., Kobayashi, T., Ueyama, T., Shirai, Y. and Saito, N.
  • Journal Title: -Importance of Kinase Activity and Binding to AP2α-Biochem. J 409 Pages: 471-479
  • Peer Reviewed
• [Journal Article] Diacylglycerol kinase β accum ulates on the perisynaptic site of medium spiny neurons in the striatum. (2008)
  • Author(s): Hozumi, Y., 他
  • Journal Title: Eur, J. Neurosci. 28 Pages: 2409-2422
  • Peer Reviewed
• [Journal Article] Ca2+ oscillation induced by P2Y2 receptor activation and its regulation by a neuron-specific subtype of PKC (γPKC) (2008)
  • Author(s): Ashida, N, 他
  • Journal Title: Neurosci. Lett. 446 Pages: 123-128
  • Peer Reviewed
• [Journal Article] Metabotropic glutamate receptor subtype-1 is essential for in vivogrowth of melanoma. (2008)
  • Author(s): Ohtani, Y., 他
  • Journal Title: Oncogene 27 Pages: 7162-7170
  • Peer Reviewed
• [Journal Article] A newly identified role for N0X1/NADPH oxidase in inflammatory pain (2008)
  • Author(s): Ibi, M., 他
  • Journal Title: J. Neurosci. 28 Pages: 9486-9494
  • Peer Reviewed
• [Journal Article] Minireview : Protein kinase Ce-function in neurons. (2008)
  • Author(s): Shirai, Y., 他
  • Journal Title: FEBS J. 275 Pages: 3988-3994
  • Peer Reviewed
• [Journal Article] Enzymological analysis of mutant protein kinase Cγ causing spinocerebellar ataxia type 14 and its dysfunction in Ca^<2+>homeostasis (2008)
  • Author(s): Adachi, N., 他
  • Journal Title: J. Biol. chem 283 Pages: 19854-19863
  • Peer Reviewed
• [Journal Article] Identification of SF-1/Ad4BP gene expression modulators by large scale gain and loss of function studies (2008)
  • Author(s): Sakai, N., 他
  • Journal Title: J. Endocrinol. 198 Pages: 489-497
  • Peer Reviewed
• [Journal Article] Sequential Binding of Cytosolic Phox Complex to Phagosomes through Regulated Adaptor Proteins : Evaluation Using the Novel Monomeric Kusabira-Green System and Live Imaging of Phagocytosis (2008)
  • Author(s): Ueyama, T., 他
  • Journal Title: J. Immunol. 181 Pages: 629-640
  • Peer Reviewed
• [Journal Article] Lck-dependent tyrosine phosphorylation of DGK alpha regulatesits membrane association in T cells (2008)
  • Author(s): Merino, E., 他
  • Journal Title: J. Immunol. 180 Pages: 5805-5815
  • Peer Reviewed
• [Journal Article] Immunogold electron microscopic demonstration of distinct submembranous localization of the activated. γPKC depending on thestim ulation (2008)
  • Author(s): Oyasu, M., 他
  • Journal Title: J. Histochem. Cytochem. 56 Pages: 253-265
  • Peer Reviewed
• [Journal Article] Synthesis, Conformational Analysis, and Biological Evaluation ofl -Hexyl-indolactam-V1 0 as a Selective Activator for Novel Protein Kinase C Isozymes. (2008)
  • Author(s): Yanagita, RC, 他
  • Journal Title: J. Med. Chem 51 Pages: 46-56
  • Peer Reviewed
• [Journal Article] Regulation of Clathrin Dependent Endocytosis by Diacylglycerolkinaseδ-Importance of Kinase Activity and Binding to AP2α- (2008)
  • Author(s): Kawasaki, T.
  • Journal Title: Biochem. J. 409 Pages: 471-479
  • Peer Reviewed
• [Journal Article] Synthesis, Conformalional Analysis, and Biological Evaluation of 1-Hexyl-indolactam-V10 as a Selective Activator for Novel Protein Kinase C Isozymes (2008)
  • Author(s): Ryo C., et al.
  • Journal Title: J. Med. Chem. 512 Pages: 46-56
  • Peer Reviewed
• [Journal Article] Immunogold electron microscopic demonstration of distinct submembranous localization of the activated. γPKC depending on the stimulation (2008)
  • Author(s): Oyasu, M., et al.
  • Journal Title: J. Histochem. Cytochem. 56 Pages: 253-265
  • Peer Reviewed
• [Journal Article] Lck-dependent tyrosine phosphorylation of DGK alpha regulatesits membrane association in T cells (2008)
  • Author(s): Merino, E., et al.
  • Journal Title: J. Immunol. (印刷中)
  • Peer Reviewed
• [Journal Article] Aggregate Formation of Mutant Protein Kinase C Gamma Found in Spinocerebellar Ataxia Type 14 Impairs Ubiquitin Proteasome System and Induces Endoplasmic Reticulum Stress Eur (2007)
  • Author(s): Seki, T., Takahashi, T., Adachi, N., Shimahara, T., Abe, N., Saito, N. and Sakai N.
  • Journal Title: J. Neurosci 26 Pages: 3126-3140
  • Peer Reviewed
• [Journal Article] A novel PIP2 binding of εPKC and its contribution to the neurite induction ability (2007)
  • Author(s): Shirai, Y., Murakami, T., Kuramasu, M., Iijima L., and Saito, N.
  • Journal Title: J. Neurochem 102 Pages: 1635-1644
  • Peer Reviewed
• [Journal Article] A regulated adaptor function of p40^<phox>: distinct p67^<phox> membrane targeting by p40^<phox> and by p47^<phox> (2007)
  • Author(s): Ueyama T, et al
  • Journal Title: Mol. Biol. Cell 18 Pages: 441-454
  • Peer Reviewed
• [Journal Article] A novel PIP2 binding of εPKC and its contribution to the neurite induction ability (2007)
  • Author(s): Shirai, Y., et al.
  • Journal Title: J. Neurochem. 102 Pages: 1635-1644
  • Peer Reviewed
• [Journal Article] Aggregate Formation of Mutant Protein Kinase C Gamma Found in Spinocerebellar Ataxia Type 14 Impairs Ubiquitin Proteasome System and Induces Endoplasmic Reticulum Stress (2007)
  • Author(s): Seki, T., et al.
  • Journal Title: Eur. J. Neurosci. 26 Pages: 3126-3140
  • Peer Reviewed
• [Journal Article] Regulation of Clathrin Dependent Endocytosis by Diacylglycerol kinaseδ-Importance of Kinase Activity and Binding to AP2α- (2007)
  • Author(s): Kawasaki, T., et al. Biochem. J. 409: 471-479, 2008
  • Journal Title: Biochem. J. 18 Pages: 441-454
  • Peer Reviewed
• [Journal Article] A Simple Analog of Tumor-promoting Aplysiatoxin Is an Antineoplastic Agent rather than a Tumor Promoter : Development of a Synthetically Accessible PKC Activator with Bryostatin-like Activity
  • Author(s): Yu Nakagawa, Y. Yanagita, RC, Hamada, N. Murakami, A. Takahashi, H. Saito, N. Nagai, H. and Irie, K.
  • Journal Title: J Am. Chem. Soc (in press)
  • Peer Reviewed
• [Journal Article] Duox maturation factors form cell surface complexes with Duoxaffecting the specificity of reactive oxygen species generation.
  • Author(s): Morand S, 他
  • Journal Title: FASEB J. (掲載確定) (印刷中)
  • Peer Reviewed
• [Presentation] マウス初代培養表皮細胞におけるRac3のRac1代償機能 (2009)
  • Author(s): 清水彩、上山健彦、坂原瑞穂、饗場篤、齋藤尚亮
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-16
• [Presentation] 神経特異的ジアシルグリセロールキナーゼDGKβの機能解析 (2009)
  • Author(s): 上月健、白井康仁、掛札賢一、大八木篤、堀江恭二、嶋澤雅光、福永浩司、竹田潤二、齋藤尚亮、原英彰
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] 気分障害と神経特異的ジアシルグリセロール (2009)
  • Author(s): 白井康仁、齋藤尚亮
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] Sequential binding of cytosolic phox complex to phagosomes through regulated adaptor proteins : evaluation using the novel monomeric Kusabira-Green(mKG) system and liveimaging of phagocytosis. (2008)
  • Author(s): Ueyama, T., 他
  • Organizer: Gordon Research Conference
  • Place of Presentation: ボストン(米国)
  • Year and Date: 2008-06-04
• [Presentation] Sequential targeting of cytosolic phox proteins to phagosomes through regulated adaptor proteins during Fc□R-mediated phagocytosis (2008)
  • Author(s): Ueyama,T., Kusakabe,T., Karasawa,S., Kawasaki,T., Shimizu,A., Son,eong-hyun., Leto L.Thomas
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] 神経特異的ジアシルグリセロールキナーゼDGKβの機能解析 (2008)
  • Author(s): 白井康仁、上月健、掛札賢一、大八木篤、堀江恭二、嶋澤雅光、竹田潤二、齋藤尚亮、原英彰
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] NADPH oxidaseファミリーの活性化機構とその生理機能 (2008)
  • Author(s): 上山健彦
  • Organizer: 第3回グローバルCOE研究討論会
  • Place of Presentation: 淡路島(兵庫)
• [Presentation] Sequential binding of cytosolic phox complex to phagosomes through regulated adaptor proteins : evaluation using the novel monomeric Kusabira-Green(mKG)system and liveimaging of phagocytosis (2008)
  • Author(s): Ueyama,T., Kusakabe,T., Karasawa,S., Kawasaki,T., Shimizu,A., Son, Jeong-hyun., Leto,L.Thomas., Miyawaki,A., Saito,N.
  • Organizer: Gordon Research Conference
  • Place of Presentation: ボストン
• [Presentation] Recessive embryonic lethality in mutant mice carrying a gene trap in intron 3 of RKIP-1 gene(92) (2008)
  • Author(s): Uo,M., Ohmori,S., Nakao,K., Saito,N.
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] Differential regulation of dual oxidase 1 by dual activator 1 splicing variants (2008)
  • Author(s): Tsujibe,S., Ueyama,T., Shirai,Y., Leto L. Thomas., Saito,N.
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] Enzymological properties of PKCγ mutants found in spinocerebellar ataxia 14(SCA14) and its involvement in neuronal death (2007)
  • Author(s): Saito, N., et al.
  • Organizer: International symposium on cell signaling and gene regulation
  • Place of Presentation: Tainan, Taiwan
  • Year and Date: 2007-11-18
• [Presentation] 脊髄小脳失調症14型における変異PKCγのC1Aとキナーゼドメインを介した分子間相互作用・凝集体形成傾向の重要性 (2007)
  • Author(s): 高橋英之、足立直子、杉本卓弥、中北順也、関貴弘、入江一浩、酒井規雄、齋藤尚亮
  • Organizer: 第112回日本薬理学会近畿部会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)
  • Year and Date: 2007-11-16
• [Presentation] Live imaging of PKC signaling and its implication in neuronal disease (2007)
  • Author(s): Naoaki Saito, et al.
  • Organizer: 14^<th> Congress of Ca^<2+> binding proteins & Ca^<2+> function in health & disease
  • Place of Presentation: La Palma, Spain
  • Year and Date: 2007-10-18
• [Presentation] ヒトケラチノサイトにおけるTNF-αによるNGF 分泌促進作用とそのシグナル (2007)
  • Author(s): 伝達機能, 高岡幸二、白井康仁、齋藤尚亮
  • Organizer: 第111回日本薬理学会近畿部会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-06-15
• [Presentation] DG-PKCシグナル系の可視化とその異常による疾患 (2007)
  • Author(s): 斎藤尚亮, 他
  • Organizer: 第49回日本脂質生化学会
  • Place of Presentation: 北海道大学
  • Year and Date: 2007-06-06
• [Presentation] Enzymological properties of PKCγ mutants found in spinocerebellar ataxia 14(SCA14) and its involvement in neuronal death (2007)
  • Author(s): Saito,N., Adachi,N., Takahashi,H., Kobayashi,T., Seki,T. Sakai,N.
  • Organizer: International symposium on cell signaling and gene regulation
  • Place of Presentation: Taiwan
• [Presentation] Live imaging of PKC signaling and its implication in neuronal disease (2007)
  • Author(s): Naoaki Saito
  • Organizer: 14^<th> Congress of Ca2+ binding proteins & Ca2+ function in health & disease
  • Place of Presentation: La Palma Spain
• [Presentation] Dysfunction of intracellular Ca2+ regulation in SCA14 (2007)
  • Author(s): Adachi,N., Kobayashi,T., Seki,T., Sakai,N., Saito, N.
  • Organizer: 14^<th> Congress of Ca2+ binding proteins & Ca2+ function in health & disease
  • Place of Presentation: La Palma Spain
• [Presentation] Clarification of regulatory mechanism of Orail(SOCs)by PKC (2007)
  • Author(s): Kawasaki,T., Ueyama,T., Shirai,Y., Saito, N.
  • Organizer: 14^<th> Congress of Ca2+ binding proteins & Ca2+ function in health & disease
  • Place of Presentation: La Palma Spain
• [Presentation] 緑色蛍光蛋白(GFP)発現バイオ試料の半導体レーザ超短パルス光源による2光子イメージング (2007)
  • Author(s): 佐藤綾耶、高島啓次郎、郭亨長、牟禮勝仁、横山弘之、坪川宏、齋藤尚亮
  • Organizer: 第68回日本応用物理学会学術講演会
  • Place of Presentation: 北海道
• [Presentation] c-Ab1, a tyrosine kinase involved in chronic myeloid leukemia, regulates nucleo-cytoplasmic shuttling of DGKαand cell cycle (2007)
  • Author(s): Shirai,Y., Matsubara,T., Saito, N.
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Indian Wells CA
• [Presentation] A regulated adaptor function of p40phox : Intramolecular interaction (PX-PB1 domain)within p40phox (2007)
  • Author(s): Ueyama,T., Tatsuno,T., Kawasaki,T., Thomas L.Leto., Saito, N.
  • Organizer: Gordon Research Conference
  • Place of Presentation: ロードアイランド
• [Presentation] 核内脂質シグナル及び核移行蛋白質の可視化システムを用いた細胞周期機構の解明-DGK の核-細胞質間移行機構と核内における機能に着目して- (2007)
  • Author(s): 白井康仁、松原岳大、齋藤尚亮
  • Organizer: 第49回日本脂質生化学会
  • Place of Presentation: 北海道
• [Presentation] D核内脂質シグナル及び核移行蛋白質の可視化システムを用いた細胞周期機構の解明-DGKの核-細胞質間移行機構と核内における機能に着目して (2007)
  • Author(s): 白井康仁、松原岳大、齋藤尚亮
  • Organizer: 第49回日本脂質生化学会
  • Place of Presentation: 北海道
• [Presentation] DG-PKCシグナル系の可視化とその異常による疾患 (2007)
  • Author(s): 齋藤尚亮、白井康仁、松原岳大、足立直子、高橋英之、酒井規雄
  • Organizer: 第49回日本脂質生化学会
  • Place of Presentation: 北海道
• [Presentation] RalAはηPKCによるケラチノサイトの扁平化に必須である。 (2006)
  • Author(s): 白井康仁、盛岡祥子、大辻千裕、吉野健一、酒井規雄、上山健彦、齋藤尚亮
  • Organizer: 第113回日本薬理学会近畿部会
  • Place of Presentation: 岡山
  • Year and Date: 2006-06-20
• [Presentation] P2Y受容体を介するγPKCのオシレーション機構の解明 (2006)
  • Author(s): 芦田典明、上山健彦、力武恭子、白井康仁、衛藤三佳、近藤威、甲村英二、齋藤尚亮
  • Organizer: 第113回日本薬理学会近畿部会
  • Place of Presentation: 岡山
  • Year and Date: 2006-06-20