1999 Fiscal Year Annual Research Report

癌抑制遺伝子の作用機構

Research Project

Project/Area Number	06283215
Research Institution	The University of Tokyo
Principal Investigator	秋山徹東京大学, 分子細胞生物学研究所, 教授 (70150745)
Keywords	癌抑制遺伝子 / 大腸癌 / APC / Wntシグナル / β-catenin / TCF / G蛋白質
Research Abstract	(1)Wntシグナル伝達経路は癌化や形態形成に重要な役割をはたしている。Wntシグナルによりβ-cateninは安定化しTCF/LEFと複合体をつくり標的遺伝子の転写を活性化する。我々は、新規β-catenin結合蛋白質を見出し(ICATと命名)、ICATがβ-cateninとTCFの相互作用を阻害することにより標的遺伝子の転写活性化を阻害することを明らかにした。さらに、ICATはWntシグナルを阻害することによりXenopusの体軸形成を阻害する活性をもつことを明らかにした。(2)APC遺伝子は家族性大腸腺腫症の原因遺伝子で一般の大腸癌の大多数でも変異をおこしている。我々は、APC遺伝子産物のarmadilloリピートに結合する新規蛋白質を見出しAsefと命名した。APCとAsefは、大腸、海馬など在が一致し、β-cateninを含む複合体を形成していると考えられた。Asefは、Dblファミリーに属すRac特異的なguanine nucleotide exchange factor(GEF)で、APCと結合することにより活性化した。さらに、MDCK細胞にAsefを過剰発現するとAPC依存的に形態変化、rufflingを誘導した。APC-Asef複合体はアクチン細胞骨格ネットワーク、細胞形態、細胞運動などの制御に関与している可能性があると考えられた。

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-2 and BCL-XL"Oncogene. 18. 487-494 (1999)
[Publications] T. Tezuka, et al.: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methl-D0aspartate receptor subunit NR2A"Proc. Natil. 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 Cytochem. 47. 1149-1158 (1999)
[Publications] C.R, Badal, et al.: "Localization 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 discs 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 hDLB"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

癌抑制遺伝子の作用機構

Principal Investigator

秋山 徹 東京大学, 分子細胞生物学研究所, 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-2 and BCL-XL"Oncogene. 18. 487-494 (1999)

[Publications] T. Tezuka, et al.: "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methl-D0aspartate receptor subunit NR2A"Proc. Natil. 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 Cytochem. 47. 1149-1158 (1999)

[Publications] C.R, Badal, et al.: "Localization 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 discs 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 hDLB"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, 分子細胞生物学研究所, 教授 (70150745)