2002 年度実績報告書

細胞周期の制御異常

研究課題

研究課題/領域番号	12215020
研究機関	東京大学
研究代表者	秋山徹東京大学, 分子細胞生物学研究所, 教授 (70150745)
研究分担者	畑裕東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (80313237)
キーワード	癌抑制遺伝子 / APC / ICAT / Asef / KAP3 / 裏打ち蛋白 / BAOP1 / MAG1 / PAPIN
研究概要	がん細胞における細胞周期制御異常の機構を明らかにすることを目的として、大腸癌のがん抑制遺伝子APCおよびBAP1/MAGI・PAPINなどの上皮細胞膜裏打ち蛋白質の機能を解析し、以下の知見を得た。1)大腸がん細胞で発現している変異APC断片は、Rac特異的GEF分子Asefを恒常的に活性化して細胞接着の低下、細胞運動の異常な亢進を引き起こしていることを明らかにした。正常APCを発現するがん細胞ではAsefの恒常的活性化は起こっていなかった。2)APCは、KAP3を介してKIF3A/3Bと複合体を形成し、微小管に沿って移動して細胞先端に集積するが、Asefも先導端に集積することを見出した。APCとAsefは先導端のみでなく細胞接着面、ラッフリング膜などでも局在が一致した。3)癌遺伝子Bc19の産物と相同性のあるB9Lを見出し、β-cateninに結合してβ-catenin-TCF複合体による転写活性化を促進することを明らかにした。4)APCにRing fingerタイプのユビキチンligaseが結合し、ユビキチン化-プロテアソームによる分解を引き起こすことを明らかにした。5)β-cateninおよびTGF-βの標的遺伝子を単離した。6)上皮細胞間結合のtight junctionの裏打ち蛋白質BAP1/MAGI-1がBAP1/MAGI-1と協働してtight junctionにおける分子の透過性を制御する可能性を明らかにした。7)BAP1/MAGI-1に結合する新規分子Caromが、細胞極性が確立したあとにはadherence junctionに局在してCASKと相互作用することを明らかにした。8)I型肺胞上皮細胞に発現している膜貫通蛋白質T1αとReceptor for advanced glycation endproducts (RAGE)が、I型肺胞上皮細胞の極性マーカーとして使用できることを明らかにした。

研究成果

(16件)

すべてその他

すべて文献書誌 (16件)

[文献書誌] T.Okabe: "RICS, a novel GTPase-Activating Protein for Cdc42 and Rac1, is involved in the b-catenin-N-cadherin and NMDA receptor signaling"J. Biol. Chem.. (in press).
[文献書誌] Y.Kawasaki: "Mutated APC and Asef are Involved in Migration of Colorectal Tumor Cells"Nature Cell Biology. 5(3). 211-215 (2003)
[文献書誌] T.Jimbo: "Identification of link between the Tumor Suppressor APC and the Kinesin Superfamily of Proteins"Nature Cell Biol.. 4. 323-327 (2002)
[文献書誌] T.Sekiya: "Overexpression of Icat Induces G2 Arrest and Cell Death in Tumor Cells Mutant for APC, β-catenin or Axin"Cancer Res.. 62. 3322-3326 (2002)
[文献書誌] B.C.Roy: "SPAL, a Rap-specific GTPase Activating Protein, is Present in the NMDA receptor-PSD-95 Complex in the Hippocampus"Genes Cells. 7. 607-617 (2002)
[文献書誌] K.Kohu: "The SH3, HOOK and Guanylate Kinase-like Domains of hDLG are Important for its Cytoplasmic Localization"Genes Cells. 7. 707-715 (2002)
[文献書誌] Kim M.: "Binding of the mammalian homolog of he Drosophila discs large tumor suppressor protein to the ribosome receptor"Biochem Biophys Res Commun.. 294. 1151-1154 (2002)
[文献書誌] T.Koyama: "Mutation and expression of the β-catenin-interacting rotein ICAT in human colorectal tumors"Jpn. J. Clin. Oncol.. 358-362 (2002)
[文献書誌] F.Ogawa: "Binding of the Human Homolog of the Drosophila Discs Large Tumor Suppressor Protein to the Mitochondrial Ribosomal Protein MRP-S34"Biochem. Biophys. Res. Commun.. 294. 1151-1154 (2002)
[文献書誌] Takemura M.: "Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23"Exp. Cell Res.. 276. 233-241 (2002)
[文献書誌] H.Seo: "Incorporation of DUF/FACT into chromatin enhances the accessibility of nucleosomal DNA"Biochem. Biophys. Res. Commun.. (in press). (2002)
[文献書誌] Ohno H.: "Localization of p0071-interacting proteins, plakophilin-related armadillo-repeat protein-interacting protein and ERBIN, in epithelial cells"Oncogene. 21. 7042-7049 (2002)
[文献書誌] Yao I.: "Synaptic localization of SAPAP1, a synaptic membrane-associated protein"Genes Cells. (in press).
[文献書誌] Hirabayashi S.: "C2PA is a nuclear protein implicated in heat shock response"J. Cell. Biochem. 87. 65-74 (2002)
[文献書誌] Yao I.: "Synaptic and nuclear localization of brain-enriched guanylate kinase-associated protein"J. Neurosci.. 22. 5354-5364 (2002)
[文献書誌] Iida J.: "Synaptic localization of membrane-associated guanylate kinase-interacting protein mediated by the pleckstrin homology domain"Eur. J. Neurosci.. 15. 1493-1498 (2002)

2002 年度 実績報告書

細胞周期の制御異常

研究代表者

秋山 徹 東京大学, 分子細胞生物学研究所, 教授 (70150745)

研究成果

[文献書誌] T.Okabe: "RICS, a novel GTPase-Activating Protein for Cdc42 and Rac1, is involved in the b-catenin-N-cadherin and NMDA receptor signaling"J. Biol. Chem.. (in press).

[文献書誌] Y.Kawasaki: "Mutated APC and Asef are Involved in Migration of Colorectal Tumor Cells"Nature Cell Biology. 5(3). 211-215 (2003)

[文献書誌] T.Jimbo: "Identification of link between the Tumor Suppressor APC and the Kinesin Superfamily of Proteins"Nature Cell Biol.. 4. 323-327 (2002)

[文献書誌] T.Sekiya: "Overexpression of Icat Induces G2 Arrest and Cell Death in Tumor Cells Mutant for APC, β-catenin or Axin"Cancer Res.. 62. 3322-3326 (2002)

[文献書誌] B.C.Roy: "SPAL, a Rap-specific GTPase Activating Protein, is Present in the NMDA receptor-PSD-95 Complex in the Hippocampus"Genes Cells. 7. 607-617 (2002)

[文献書誌] K.Kohu: "The SH3, HOOK and Guanylate Kinase-like Domains of hDLG are Important for its Cytoplasmic Localization"Genes Cells. 7. 707-715 (2002)

[文献書誌] Kim M.: "Binding of the mammalian homolog of he Drosophila discs large tumor suppressor protein to the ribosome receptor"Biochem Biophys Res Commun.. 294. 1151-1154 (2002)

[文献書誌] T.Koyama: "Mutation and expression of the β-catenin-interacting rotein ICAT in human colorectal tumors"Jpn. J. Clin. Oncol.. 358-362 (2002)

[文献書誌] F.Ogawa: "Binding of the Human Homolog of the Drosophila Discs Large Tumor Suppressor Protein to the Mitochondrial Ribosomal Protein MRP-S34"Biochem. Biophys. Res. Commun.. 294. 1151-1154 (2002)

[文献書誌] Takemura M.: "Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23"Exp. Cell Res.. 276. 233-241 (2002)

[文献書誌] H.Seo: "Incorporation of DUF/FACT into chromatin enhances the accessibility of nucleosomal DNA"Biochem. Biophys. Res. Commun.. (in press). (2002)

[文献書誌] Ohno H.: "Localization of p0071-interacting proteins, plakophilin-related armadillo-repeat protein-interacting protein and ERBIN, in epithelial cells"Oncogene. 21. 7042-7049 (2002)

[文献書誌] Yao I.: "Synaptic localization of SAPAP1, a synaptic membrane-associated protein"Genes Cells. (in press).

[文献書誌] Hirabayashi S.: "C2PA is a nuclear protein implicated in heat shock response"J. Cell. Biochem. 87. 65-74 (2002)

[文献書誌] Yao I.: "Synaptic and nuclear localization of brain-enriched guanylate kinase-associated protein"J. Neurosci.. 22. 5354-5364 (2002)

[文献書誌] Iida J.: "Synaptic localization of membrane-associated guanylate kinase-interacting protein mediated by the pleckstrin homology domain"Eur. J. Neurosci.. 15. 1493-1498 (2002)

2002 年度実績報告書

秋山徹東京大学, 分子細胞生物学研究所, 教授 (70150745)