1999 Fiscal Year Annual Research Report

NMDA受容体と癌抑制遺伝子産物APCおよびDLGファミリーの複合体形成の意義

Research Project

Project/Area Number	11470039
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	The University of Tokyo
Principal Investigator	秋山徹東京大学, 分子細胞学研究所, 教授 (70150745)
Keywords	神経 / 海馬 / NMAD受容体 / 癌抑制遺伝子 / APC / DLG / PSD-95
Research Abstract	NMDA 受容体と癌抑制遺伝子産物APC およびDLG ファミリーの複合体形成の意義を明らかにするための研究を行い以下のような結果を得た。 1)DLG 遺伝子欠失マウスを作製したところ生後約5時間程度で死亡することが明らかとなった。脳の形態学的検討を行ったが特に目立った異常は見出されなかった。今後DLGと結合するAMPA型受容体などについて生化学的、分子生物学的な解析を進める。また、コンディショナルターゲッティングマウスの作製も進める。 2)DLG、PSD-95に結合するRAP1特異的GAP活性をもつ分子をSPALと名づけ解析を進めた結果、培養海馬神経細胞を用いた実験によりNMDA刺激により約半数の分子が脱リン酸化を起こすことを明らかにした。しかし、SPALのGAP活性の変化は検出されなかった。リン酸化が他の分子との相互作用、局在の変化等に及ぼす影響について検討を進めている。ターゲッティングマウスの作製も継続している。また、SPALのロイシンジッパーに結合する蛋白質およびPDZドメインに結合する蛋白質の候補を同定した。 3)APCのアルマジロリピートドメインに結合することを見出した新規分子(Asefと命名)がRac特異的GEF活性をもつことを明らかにした。Asefは海馬、嗅球、小脳などでAPCと局在が一致した。また、培養海馬神経細胞の細胞体およびシナプスに濃縮して存在することを見出した。さらに、ノックアウトマウスの作製を試みキメラマウスを作製した。

Research Products
(13 results)

All Other

All Publications (13 results)

[Publications] F.Hamada,et al.: "Negative regulation of Wingless signaling by D-Axin、a Drosophila homologue of Axin"Science. 283. 1739-1742 (1999)
[Publications] F.Hamada,et al.: "Identification and Characterization of D-APC2,a Novel Drosophila Homologue of the Tumor Suppressor APC"Genes Cells. 4. 465-474 (1999)
[Publications] T.Yamochi,et al.: "Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied by downregulation of BCL-XL"Oncogene. 18. 487-494 (1999)
[Publications] T.Tezuka,et al.: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A"Proc.Natl.Acad.Sci.USA. 96. 435-440 (1999)
[Publications] T.Senda,et al.: "Localization of MCC (mutated in colorectal cancer) in various tissues of mice and its involvement in cell differentiation"J Histochem Cyochem. 47. 1149-1158 (1999)
[Publications] C.R,Badal,et al.: "Localozation of the GAP family SPAL in the Rat Esophagus and Heart"Med.Electron Microsc.. 32. 20-24 (1999)
[Publications] T.Suzuki,et al.: "Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila descs large tumor suppressor protein,hDLG,and perturbs its function in cell growth control"Oncogene. 18. 5967-5972 (1999)
[Publications] M.Takemura,et al.: "Nucleolar protein B23.1 binds to retinoblastoma protein and synergistically stimulates DNA polymerase alpha activity"J.Biochem.. 125. 904-909 (1999)
[Publications] T.Ishidate,et al.: "The APC-hDLG Complex Negatively Regulates Cell Cycle Progression from the G0/G1 to S Phase"Oncogene. 19. 365-372 (2000)
[Publications] H.Nakagawa,et al.: "EB3,a novel member of the EB1 family preferentially expressed in the central nervous system,binds to a CNS-specific APC homologue"Oncogene. 19. 210-216 (2000)
[Publications] H.Nakagawa,et al.: "APCL,a central nervous system-specific homolog of adenomatous polyposis coli tumor suppressor,binds to p53-binding protein 2 and translocates it to the perinucleus"Cancer Res.. 60. 101-105 (2000)
[Publications] T.Senda,et al.: "Expression of APC in the mouse kidney and its colocalization with b-catenin and hDLG"J.Histochem.Cytochem.. (in press).
[Publications] K.Kawahara,et al.: "Downregulation of b-catenin by the Colorectal Tumor Suppressor APC Requires Association with Axin and b-catenin"J.Biol.Chem.. (in press).

1999 Fiscal Year Annual Research Report

NMDA受容体と癌抑制遺伝子産物APCおよびDLGファミリーの複合体形成の意義

Principal Investigator

秋山 徹 東京大学, 分子細胞学研究所, 教授 (70150745)

Research Products

[Publications] F.Hamada,et al.: "Negative regulation of Wingless signaling by D-Axin、a Drosophila homologue of Axin"Science. 283. 1739-1742 (1999)

[Publications] F.Hamada,et al.: "Identification and Characterization of D-APC2,a Novel Drosophila Homologue of the Tumor Suppressor APC"Genes Cells. 4. 465-474 (1999)

[Publications] T.Yamochi,et al.: "Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied by downregulation of BCL-XL"Oncogene. 18. 487-494 (1999)

[Publications] T.Tezuka,et al.: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A"Proc.Natl.Acad.Sci.USA. 96. 435-440 (1999)

[Publications] T.Senda,et al.: "Localization of MCC (mutated in colorectal cancer) in various tissues of mice and its involvement in cell differentiation"J Histochem Cyochem. 47. 1149-1158 (1999)

[Publications] C.R,Badal,et al.: "Localozation of the GAP family SPAL in the Rat Esophagus and Heart"Med.Electron Microsc.. 32. 20-24 (1999)

[Publications] T.Suzuki,et al.: "Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila descs large tumor suppressor protein,hDLG,and perturbs its function in cell growth control"Oncogene. 18. 5967-5972 (1999)

[Publications] M.Takemura,et al.: "Nucleolar protein B23.1 binds to retinoblastoma protein and synergistically stimulates DNA polymerase alpha activity"J.Biochem.. 125. 904-909 (1999)

[Publications] T.Ishidate,et al.: "The APC-hDLG Complex Negatively Regulates Cell Cycle Progression from the G0/G1 to S Phase"Oncogene. 19. 365-372 (2000)

[Publications] H.Nakagawa,et al.: "EB3,a novel member of the EB1 family preferentially expressed in the central nervous system,binds to a CNS-specific APC homologue"Oncogene. 19. 210-216 (2000)

[Publications] H.Nakagawa,et al.: "APCL,a central nervous system-specific homolog of adenomatous polyposis coli tumor suppressor,binds to p53-binding protein 2 and translocates it to the perinucleus"Cancer Res.. 60. 101-105 (2000)

[Publications] T.Senda,et al.: "Expression of APC in the mouse kidney and its colocalization with b-catenin and hDLG"J.Histochem.Cytochem.. (in press).

[Publications] K.Kawahara,et al.: "Downregulation of b-catenin by the Colorectal Tumor Suppressor APC Requires Association with Axin and b-catenin"J.Biol.Chem.. (in press).

秋山徹東京大学, 分子細胞学研究所, 教授 (70150745)