1999 年度実績報告書

がんの発生、発達に関する情報伝達の解析

研究課題

研究課題/領域番号	10152101
研究機関	東京大学
研究代表者	福井泰久東京大学, 大学院・農学生命科学研究科, 教授 (00181248)
研究分担者	黒崎知博関西医科大学, 医学部, 教授 (50178125) 稲垣昌樹愛知県がんセンター研究所, 生化学部, 部長(研究職) (30183007) 一條秀憲東京医科歯科大学, 歯学部, 教授 (00242206) 田村真理東北大学, 加齢医学研究所, 教授 (20124604) 白井隆一奈良先端大学, 大学院・物質科学教育研究センター, 助教授 (80183838)
キーワード	リン脂質 / ホシファテシジルイノシトールキナーゼ / 組織応答 / 分化 / アダプター / イノシトールリン脂質 / MAPキナーゼ / ホスホリパーゼ
研究概要	膜の構成成分であるリン脂質をはじめとする脂質が細胞の分化・増殖の調節に関わっていることは最近の研究から明らかにされつつある。リン脂質の代謝酵素PI3キナーゼは多機能2次メッセンジャーPIP_3を生じる。また、PLCはDAGおよびIP_3という重要な2次メッセンジャーを生じる。これらの下流には細胞骨格系や種々のキナーゼを介した情報伝達系の調節が位置している。従って、これらの役割を明らかにしていけば、がん細胞の成り立ちを解析でき、がんに対抗するための手段を見いだせると考えられる。本研究は8人の班員がそれぞれお互いに協力しつつ、以下のような成果を挙げた。 1)印環細胞がんの発生にはPI3キナーゼが関与しており、その下流因子p38が重要な役割をしていること、その阻害剤が印環細胞がん抑制に有効な可能性を示した。 2)PIP_3の2位は天然には不飽和脂肪酸が占めているが、飽和脂肪酸でも短鎖であれば生活性を持つことを示し、今後のPIP_3アナログ作成を容易にした。 3)PLCに関してδ4の調節機構とその生理的役割を明らかにするとともに、新規タンパク質L2を同定し、その役割について検討した。 4)PKCηのノックアウトマウスを作成し、PKCηが発がんプロモーションの抑制に関与していることを明らかにした。 5)BLNKはPLC-γ2と結合し、活性化するが、cb1はこれと拮抗することにより、PLC-γ2を負に調節していることを明らかにした。 6)PPC2一β1はMKKKの一種であるTAK1シグナル伝達を負に制御することを明らかにした。 7)酵母two-hybrid法を用いて、ビメンチン、GFAP、デスミン、およびケラチン18と結合する蛋白質を探索し、いくつかの候補タンパク質を得た。 8)ASK1のTNF-TRAF2系による活性化機構を明らかにするとともに、ASK1の下流因子JNK、p38の細胞応答における役割を明らかにした。

研究成果

(32件)

すべてその他

すべて文献書誌 (32件)

[文献書誌] Fukui, Y. et al.: "Dedifferentiation of Adenocarcinomas by Activation of Phosphatidylinositol 3-kinase"Proc Natl Acad Sci USA. 96. 4874-4879 (1999)
[文献書誌] Fukui, Y. et al.: "The structural requirement of phosphatidylinositols as substrate of phosphatidylinositol 3-kinase"Tetrahed. Let.. 40. 1693-1696 (1999)
[文献書誌] Fukui, Y. et al.: "Cyclin Dl expression mediated by phosphatidylinositol 3-kinase through mTOR-p70S6K-independent signaling in growth factor-stimulated NH3T3 fibroblasts."Mol. Cell. Biol.. 19. 1346-1358 (1999)
[文献書誌] Fukui, Y. et al.: "Increased insulin sensitivity and hypoglycemia in mice lacking p85a regulatory subunit of phosphoinositide 3-kinase."Nat. Genet.. 21. 230-235 (1999)
[文献書誌] Fukui, Y. et al.: "An evidence that a phosphatidylinositol 3,4,5-trisphosphate binding protein can function in nucleus."J. Biol Chem.. 274. 3919-3922 (1999)
[文献書誌] Fukui, Y. et al.: "Identification of protein kinase B(PKB) as a phosphatidylinositol 3,4,5-trisphosphate binding protein in Dictyostelium discoideum."Biosci. Biotech. Biochem.. 63. 368-372 (1999)
[文献書誌] Fukui, Y. et al.: "Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardimyocytes in vitro"Circulation. 100. 2373-2379 (1999)
[文献書誌] Fukui, Y. et al.: "Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase"Proc Natl Cad Sci USA. 96. 4874-4879 (1999)
[文献書誌] Fukui, Y. et al.: "In vitro and in vivo suppression of osteoclast function by adenovirus vector-induced csk gene"J Bone Miner Res.. 15. 41-51 (2000)
[文献書誌] Chida, K., Fukui. Y., et al.: "How signal transduction systems look like after recent dramatic progress"Tanpakushitsu Kakusan Koso. 100. 2373-2379 (1999)
[文献書誌] Chida, K., et al.: "Nuclear microinjection of EDTA inhibits transient expression of the lac-Z gene and stable transformation by the neomycin-resistant gene in NRK cells possibly by causing disruption of nuclear pore function. Circulation"Tissue Cult. Res. Commun.. 18. 119-123 (1999)
[文献書誌] Fukami, K., et al.: "A novel phospholipase Cδ4 splice variant as a negative regulator of PLC>"Biol. Chem.. 274. 2872-2879 (1999)
[文献書誌] Fukami, K., et al.: "Growth factor-induced promoter activation of murine phospholipase C delta 4."Eur. J. Biochem.. 267. 28-36 (2000)
[文献書誌] Tamura, S., et al.: "Proteinphosphatase 2C inactivates F-action binding of human platelet moesin."J. Biol. Chem.. 274. 26705-26712 (1999)
[文献書誌] Shirai, R., et al.: "The structural requirement of phosphatidylinositols as substrate of phosphatidylinositol 3- kinase."Tetrahedron Lett.. 40. 1693-1696 (1999)
[文献書誌] Ichijo, H., et al.: "Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblastic and chondroblastic differentiation"Mol. Biol. Cell. 10. 3801-3813 (1999)
[文献書誌] Ichijo, H., et al.: "Bcl-2 is phosphorylated and inactivated by an ASK1-JNK pathway morally activated at G2/M"Biol. Cell.. 10. 8469-8478 (1999)
[文献書誌] Ichijo, H., et al.: "Induction of apoptosis signal regulation kinase 1 (ASK1) after spinal cord injury in rats: Possible involvement of ASK1-JNK and -p38 pathways in neuronal apoptosis. Circulation"J. Neuropathol. Exp. Neurol.. 58. 442-450 (1999)
[文献書誌] Ichijo, H., et al.: "Ask mediates apoptosis cell death induced by geotaxis stress. Circulation"Oncogene. 18. 173-180 (1999)
[文献書誌] Ichijo, H., et al.: "Microtuble disfunction induced by Paclitaxel initiates apoptosis through both c-Jun N-terminal kinase (JNK)-dependent and -independent pathways in ovarian cancer cells. Circulation"J. Biol. Chem.. 274. 8208-8216 (1999)
[文献書誌] Ichijo, H., et al.: "Apoptosis inhibitory activity of cytoplasmic p21Cipl/WAF1 in monocytic differentiation"EMBO J.. 18. 1223-1234 (1999)
[文献書誌] Ichijo, H., et al.: "Triggering neuronal cell death by the in situ activation f SEK1 nuclear polyglutamine aggregations"Oncogene. 18. 2783-2788 (1999)
[文献書誌] Inagaki, M., et al.: "Identification of a novel phosphorylation site on histone H3 coupled with mitotic chromosome condensation"J. Biol. Chem.. 274. 25543-25549 (1999)
[文献書誌] Inagaki, M., et al.: "Balance between activities of Rho-kinase and Type I protein Phosphatase modulates turnover of phosphorylation and dynamics of desmin/vimentin firmaments"J. Biol. Chem.. 274. 34932-34939 (1999)
[文献書誌] Tamura. S., et al.: "Alternative promoters direct tissue-specific expression of the mouse protein phosphatase 2C β gene."Eur. J. Biochem.. 263. 736-745 (1999)
[文献書誌] Tamura. S., et al.: "Expressions of four major protein ser/thr phosphatases in human primary leukemic cells"Leukemia. 13. 595-600 (1999)
[文献書誌] Kurosaki, T., et al.: "Paired Immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1. Circulation"Oncogene. 18. 2291-2297 (1999)
[文献書誌] Kurosaki, T., et al.: "BLMK required for coupling Syk to PLC-γ2 and Racl-JNK in B cells"Immunity. 10. 117-125 (1999)
[文献書誌] Kurosaki, T., et al.: "Encoding Ca^<2+> signals by differential expression of IP_3 receptor subtypes"EMBO J.. 18. 1303-1308 (1999)
[文献書誌] Kurosaki, T., et al.: "Inhibitory modulation of B cell receptor-mediated CA^<2+> mobilization by Srchomology 2 domain-containing inositol 5'-phosphatase (SHIP)"J. Biol. Chem..
[文献書誌] Kurosaki, T., et al.: "Bruton's tyrosine kinase activity in negatively regulated by Sab, the Btk-SH3 domain binding protein"Proc. Natl. Acad. Sci. U.S.A.. 96. 6341-6346 (1999)
[文献書誌] Kurosaki, T., et al.: "In vitro and in vivo suppression of osteoclast function by adenovirus vector-induced csk gene"J Bone Miner Res.. 15. 753-760 (1999)

1999 年度 実績報告書

がんの発生、発達に関する情報伝達の解析

研究代表者

福井 泰久 東京大学, 大学院・農学生命科学研究科, 教授 (00181248)

研究成果

[文献書誌] Fukui, Y. et al.: "Dedifferentiation of Adenocarcinomas by Activation of Phosphatidylinositol 3-kinase"Proc Natl Acad Sci USA. 96. 4874-4879 (1999)

[文献書誌] Fukui, Y. et al.: "The structural requirement of phosphatidylinositols as substrate of phosphatidylinositol 3-kinase"Tetrahed. Let.. 40. 1693-1696 (1999)

[文献書誌] Fukui, Y. et al.: "Cyclin Dl expression mediated by phosphatidylinositol 3-kinase through mTOR-p70S6K-independent signaling in growth factor-stimulated NH3T3 fibroblasts."Mol. Cell. Biol.. 19. 1346-1358 (1999)

[文献書誌] Fukui, Y. et al.: "Increased insulin sensitivity and hypoglycemia in mice lacking p85a regulatory subunit of phosphoinositide 3-kinase."Nat. Genet.. 21. 230-235 (1999)

[文献書誌] Fukui, Y. et al.: "An evidence that a phosphatidylinositol 3,4,5-trisphosphate binding protein can function in nucleus."J. Biol Chem.. 274. 3919-3922 (1999)

[文献書誌] Fukui, Y. et al.: "Identification of protein kinase B(PKB) as a phosphatidylinositol 3,4,5-trisphosphate binding protein in Dictyostelium discoideum."Biosci. Biotech. Biochem.. 63. 368-372 (1999)

[文献書誌] Fukui, Y. et al.: "Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardimyocytes in vitro"Circulation. 100. 2373-2379 (1999)

[文献書誌] Fukui, Y. et al.: "Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase"Proc Natl Cad Sci USA. 96. 4874-4879 (1999)

[文献書誌] Fukui, Y. et al.: "In vitro and in vivo suppression of osteoclast function by adenovirus vector-induced csk gene"J Bone Miner Res.. 15. 41-51 (2000)

[文献書誌] Chida, K., Fukui. Y., et al.: "How signal transduction systems look like after recent dramatic progress"Tanpakushitsu Kakusan Koso. 100. 2373-2379 (1999)

[文献書誌] Chida, K., et al.: "Nuclear microinjection of EDTA inhibits transient expression of the lac-Z gene and stable transformation by the neomycin-resistant gene in NRK cells possibly by causing disruption of nuclear pore function. Circulation"Tissue Cult. Res. Commun.. 18. 119-123 (1999)

[文献書誌] Fukami, K., et al.: "A novel phospholipase Cδ4 splice variant as a negative regulator of PLC>"Biol. Chem.. 274. 2872-2879 (1999)

[文献書誌] Fukami, K., et al.: "Growth factor-induced promoter activation of murine phospholipase C delta 4."Eur. J. Biochem.. 267. 28-36 (2000)

[文献書誌] Tamura, S., et al.: "Proteinphosphatase 2C inactivates F-action binding of human platelet moesin."J. Biol. Chem.. 274. 26705-26712 (1999)

[文献書誌] Shirai, R., et al.: "The structural requirement of phosphatidylinositols as substrate of phosphatidylinositol 3- kinase."Tetrahedron Lett.. 40. 1693-1696 (1999)

[文献書誌] Ichijo, H., et al.: "Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblastic and chondroblastic differentiation"Mol. Biol. Cell. 10. 3801-3813 (1999)

[文献書誌] Ichijo, H., et al.: "Bcl-2 is phosphorylated and inactivated by an ASK1-JNK pathway morally activated at G2/M"Biol. Cell.. 10. 8469-8478 (1999)

[文献書誌] Ichijo, H., et al.: "Induction of apoptosis signal regulation kinase 1 (ASK1) after spinal cord injury in rats: Possible involvement of ASK1-JNK and -p38 pathways in neuronal apoptosis. Circulation"J. Neuropathol. Exp. Neurol.. 58. 442-450 (1999)

[文献書誌] Ichijo, H., et al.: "Ask mediates apoptosis cell death induced by geotaxis stress. Circulation"Oncogene. 18. 173-180 (1999)

[文献書誌] Ichijo, H., et al.: "Microtuble disfunction induced by Paclitaxel initiates apoptosis through both c-Jun N-terminal kinase (JNK)-dependent and -independent pathways in ovarian cancer cells. Circulation"J. Biol. Chem.. 274. 8208-8216 (1999)

[文献書誌] Ichijo, H., et al.: "Apoptosis inhibitory activity of cytoplasmic p21Cipl/WAF1 in monocytic differentiation"EMBO J.. 18. 1223-1234 (1999)

[文献書誌] Ichijo, H., et al.: "Triggering neuronal cell death by the in situ activation f SEK1 nuclear polyglutamine aggregations"Oncogene. 18. 2783-2788 (1999)

[文献書誌] Inagaki, M., et al.: "Identification of a novel phosphorylation site on histone H3 coupled with mitotic chromosome condensation"J. Biol. Chem.. 274. 25543-25549 (1999)

[文献書誌] Inagaki, M., et al.: "Balance between activities of Rho-kinase and Type I protein Phosphatase modulates turnover of phosphorylation and dynamics of desmin/vimentin firmaments"J. Biol. Chem.. 274. 34932-34939 (1999)

[文献書誌] Tamura. S., et al.: "Alternative promoters direct tissue-specific expression of the mouse protein phosphatase 2C β gene."Eur. J. Biochem.. 263. 736-745 (1999)

[文献書誌] Tamura. S., et al.: "Expressions of four major protein ser/thr phosphatases in human primary leukemic cells"Leukemia. 13. 595-600 (1999)

[文献書誌] Kurosaki, T., et al.: "Paired Immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1. Circulation"Oncogene. 18. 2291-2297 (1999)

[文献書誌] Kurosaki, T., et al.: "BLMK required for coupling Syk to PLC-γ2 and Racl-JNK in B cells"Immunity. 10. 117-125 (1999)

[文献書誌] Kurosaki, T., et al.: "Encoding Ca^<2+> signals by differential expression of IP_3 receptor subtypes"EMBO J.. 18. 1303-1308 (1999)

[文献書誌] Kurosaki, T., et al.: "Inhibitory modulation of B cell receptor-mediated CA^<2+> mobilization by Srchomology 2 domain-containing inositol 5'-phosphatase (SHIP)"J. Biol. Chem..

[文献書誌] Kurosaki, T., et al.: "Bruton's tyrosine kinase activity in negatively regulated by Sab, the Btk-SH3 domain binding protein"Proc. Natl. Acad. Sci. U.S.A.. 96. 6341-6346 (1999)

[文献書誌] Kurosaki, T., et al.: "In vitro and in vivo suppression of osteoclast function by adenovirus vector-induced csk gene"J Bone Miner Res.. 15. 753-760 (1999)

1999 年度実績報告書

福井泰久東京大学, 大学院・農学生命科学研究科, 教授 (00181248)