1990 Fiscal Year Annual Research Report

がん遺伝子の機能解析

Research Project

Project/Area Number	02262203
Research Institution	The University of Tokyo
Principal Investigator	山本雅東京大学, 医科学研究所, 助教授 (40134621)
Co-Investigator(Kenkyū-buntansha)	豊島久真男大阪大学, 微生物病研究所, 教授 (90029760) 仙波憲太郎東京大学, 医科学研究所, 助手 (70206663)
Keywords	がん遺伝子 / がん原遺伝子 / チロシンキナ-ゼ / 抗原受容体 / T細胞活性化反応 / シグナル伝達 / cーyesプロモ-タ- / cーerbBー2
Research Abstract	細胞性がん遺伝子(がん原遺伝子)産物の中でも、特にチロシンキナ-ゼ活性を有する蛋白質の機能解析と、それら遺伝子の発現制御機構に関する研究を行なった。 (1)チロシンキナ-ゼファミリ-蛋白質の機能解析。 Lyn,Fyn,FgrとErbBー2の解析を進めた。 Lynについては、Bリンパ球の抗原受容体であるsIgMならびにsIgDと会合していることを明らかにした。更に、LynがsIgM/D複合体を形成している30ー40kdと強く相互作用してそれらをin vitroで燐酸化することを示し、sIgを介するシグナル伝達に関与している可能性を指摘した。一方FynについてはTリンパ球抗原受容体と会合していることを明らかにすると共に、活性型FynをTリンパ球で発現させることにより、FynがT細胞活性化反応に関与しているという知見を予備的に得ている。Fgrについては、細胞障害活性を有する血球系細胞で発現していることを、蛋白質レベルで明らかにした。 ErbBー2ついては、そのチロシンキナ-ゼ活性を促進する因子を血清中に見いだし、有力なリガンド候補と考えて精製を進めている。一方、活性型ErbBー2による細胞がん化反応が、キナ-ゼ活性欠損型のErbBー2によって抑制されることを示し、ErbBー2によるシグナル伝達反応にErbBー2蛋白質間の相互作用が重要であることを明らかにした。 (2)転写調節機構の解析 cーyes、lynプロモ-タ-の構造と機能について解析を進め、cーyesプロモ-タ-ではSpー1結合部位が転写活性に重要であることを示し、またlynについてはT細胞での発現抑制に関与する領域を見いだした。一方cーerbBー2遺伝子が乳がんなどで過剰発現する機構について、転写レベルでの予備的研究を開始している。

Research Products

(23 results)

All Other

All Publications (23 results)

[Publications] Yoko Suda: "Induction of a variety of tumors by cーerbBー2 and clonal nature of lymphomas even with the mutated gene(Val659ーGlu659)" EMBO J. 9. 181-190 (1990)
[Publications] Frank van Leeuwen: "Mutation of the human <new>___ー protein facilitates downーmodulation by monoclonal antibodies." Oncogene. 5. 497-504 (1990)
[Publications] Jun Sukegawa: "Monoclonal antibodies to the aminoーterminal unique sequence of the cー<yesー>___ー1 gene product as specific probes of expression." Oncogene. 5. 611-614 (1990)
[Publications] Hitoshi Tsuda: "Immunohistochemical study on overexpression of cー<erbB>___ーー2 protein th human breast cancer:Its corselation with gene amplification and longーterm survival of patients." Jpn.J.Cancer Res.81. 327-332 (1990)
[Publications] Kazushi Inoue: "Specific expression of human cー<fgr>___ー in monocytes and large granular lymphocytes,effectors of natural immunity." Mol.Cell.Biol.10. 1789-1792 (1990)
[Publications] Shigeo Mori: "In Vitro and in vivo release of soluble cーerbBー2 protein from human carcinoma cells." Jpn.J.Cancer. 81. 489-494 (1990)
[Publications] Yuji Yamanashi: "Associations of B cell antigen teceptor and proteinーtyrosine kinase p56^<<lyn>___ー>." Science. 251. 192-194 (1991)
[Publications] Masatsugu Moriyama: "Expression of the cー<erb>___ーBー2 gene product in urinary bladder Cancer." J.Urology.
[Publications] Tsumeo Saga: "Scintigraphic detection of overexpressed cーerbBー2 proto oncogene products by a classーswitched murine antiーcーerbBー2 protein monoclonal antibody." Cancer Res.
[Publications] Koko Kotagiri: "Expression of <src>___ー family genes during monocytis differentication of HL 60 cells." J.Immunol.
[Publications] Tetsu Akiyama: "The transforming potential of the cーerbBー2 proteins is regulatecl by its autophospholation at the carboxyーterminal domain." Mol.Cell.Biol.
[Publications] Toshitaka Uehara: "cー<erb>___ーBー2 and cー<erb>___ーAー1 gene amphfication and cーerbBー2 protein expression in Japanese human cancers:Their relationship to the histology and diesease parameters." Jpn.J.Cancer Res.81. 620-624 (1990)
[Publications] Kentaro Semba: "Transformation of chicken Eembryo fibroblast cells by avian retroviruses containing the human <fyn>___ー gene and its mutated genes." Mol.Cel.Biol.10. 3095-3104 (1990)
[Publications] Keisuke Yuasa: "Activated c<ーerb>___ーBー2 increases metastatic potential in a low metastic clone from murine colon adenocarcinoma 26." J.NCI.82. 1633-1636 (1990)
[Publications] Nancy E.Hynes: "Oncogene transfer into cultured mouse mammary epitherial cells.Tumori genesis and interference withーlactogenic hormore action." Mol.Cell.Biol.10. 4027-4034 (1990)
[Publications] Takaya Satoh: "Accumulation of p21^<<ras>___ー> GTP in response to the stimuli of epidermal growth factor(EGF)and oncogene products with tyrosine kinase activity." Proc.Natl.Acad.Sci.87. 7926-7929 (1990)
[Publications] Takeshi Yagi: "Homologous recombination at cー<fyn>___ー locus of mouse embrynic stem cells with diphtheria toxim A fragment gene in regatwe selection." Proc.Natl.Acad.Sci.87. 9918-9922 (1990)
[Publications] Kumao Toyoshima: "The Biology and Medicine of signal Transduction" Raven Press, 6 (1990)
[Publications] Satoru Matsuda: "Genetic Basis for Carcinogenesis;Tumor Suppressor Genes and Oncogenes." Japan Sci.Soc.Press., 10 (1990)
[Publications] Kentaro Semba: "Genes and Cancer" John Wiley & Sons Ltd,11 (1990)
[Publications] George J.Tsioulias: "erbBー2 gene expression in colorectial Cancer" Jpn.J.Exp.Med., 7 (1990)
[Publications] Kumao Toyoshima: "Genetic Basis for Carcinogenesis;Tumor Suppressor Genes and Oneogenes" Japan Sci.Soc.Press., 8 (1990)
[Publications] Tadashi Yamamoto: "Mechanisms of Antimutagenesis Anticarcinogenesis “pp321ーpp329" Plenum Publishing Corporation, 9 (1990)

1990 Fiscal Year Annual Research Report

がん遺伝子の機能解析

Principal Investigator

山本 雅 東京大学, 医科学研究所, 助教授 (40134621)

Research Products

[Publications] Yoko Suda: "Induction of a variety of tumors by cーerbBー2 and clonal nature of lymphomas even with the mutated gene(Val659ーGlu659)" EMBO J. 9. 181-190 (1990)

[Publications] Frank van Leeuwen: "Mutation of the human <new>___ー protein facilitates downーmodulation by monoclonal antibodies." Oncogene. 5. 497-504 (1990)

[Publications] Jun Sukegawa: "Monoclonal antibodies to the aminoーterminal unique sequence of the cー<yesー>___ー1 gene product as specific probes of expression." Oncogene. 5. 611-614 (1990)

[Publications] Hitoshi Tsuda: "Immunohistochemical study on overexpression of cー<erbB>___ーー2 protein th human breast cancer:Its corselation with gene amplification and longーterm survival of patients." Jpn.J.Cancer Res.81. 327-332 (1990)

[Publications] Kazushi Inoue: "Specific expression of human cー<fgr>___ー in monocytes and large granular lymphocytes,effectors of natural immunity." Mol.Cell.Biol.10. 1789-1792 (1990)

[Publications] Shigeo Mori: "In Vitro and in vivo release of soluble cーerbBー2 protein from human carcinoma cells." Jpn.J.Cancer. 81. 489-494 (1990)

[Publications] Yuji Yamanashi: "Associations of B cell antigen teceptor and proteinーtyrosine kinase p56^<<lyn>___ー>." Science. 251. 192-194 (1991)

[Publications] Masatsugu Moriyama: "Expression of the cー<erb>___ーBー2 gene product in urinary bladder Cancer." J.Urology.

[Publications] Tsumeo Saga: "Scintigraphic detection of overexpressed cーerbBー2 proto oncogene products by a classーswitched murine antiーcーerbBー2 protein monoclonal antibody." Cancer Res.

[Publications] Koko Kotagiri: "Expression of <src>___ー family genes during monocytis differentication of HL 60 cells." J.Immunol.

[Publications] Tetsu Akiyama: "The transforming potential of the cーerbBー2 proteins is regulatecl by its autophospholation at the carboxyーterminal domain." Mol.Cell.Biol.

[Publications] Toshitaka Uehara: "cー<erb>___ーBー2 and cー<erb>___ーAー1 gene amphfication and cーerbBー2 protein expression in Japanese human cancers:Their relationship to the histology and diesease parameters." Jpn.J.Cancer Res.81. 620-624 (1990)

[Publications] Kentaro Semba: "Transformation of chicken Eembryo fibroblast cells by avian retroviruses containing the human <fyn>___ー gene and its mutated genes." Mol.Cel.Biol.10. 3095-3104 (1990)

[Publications] Keisuke Yuasa: "Activated c<ーerb>___ーBー2 increases metastatic potential in a low metastic clone from murine colon adenocarcinoma 26." J.NCI.82. 1633-1636 (1990)

[Publications] Nancy E.Hynes: "Oncogene transfer into cultured mouse mammary epitherial cells.Tumori genesis and interference withーlactogenic hormore action." Mol.Cell.Biol.10. 4027-4034 (1990)

[Publications] Takaya Satoh: "Accumulation of p21^<<ras>___ー> GTP in response to the stimuli of epidermal growth factor(EGF)and oncogene products with tyrosine kinase activity." Proc.Natl.Acad.Sci.87. 7926-7929 (1990)

[Publications] Takeshi Yagi: "Homologous recombination at cー<fyn>___ー locus of mouse embrynic stem cells with diphtheria toxim A fragment gene in regatwe selection." Proc.Natl.Acad.Sci.87. 9918-9922 (1990)

[Publications] Kumao Toyoshima: "The Biology and Medicine of signal Transduction" Raven Press, 6 (1990)

[Publications] Satoru Matsuda: "Genetic Basis for Carcinogenesis;Tumor Suppressor Genes and Oncogenes." Japan Sci.Soc.Press., 10 (1990)

[Publications] Kentaro Semba: "Genes and Cancer" John Wiley & Sons Ltd,11 (1990)

[Publications] George J.Tsioulias: "erbBー2 gene expression in colorectial Cancer" Jpn.J.Exp.Med., 7 (1990)

[Publications] Kumao Toyoshima: "Genetic Basis for Carcinogenesis;Tumor Suppressor Genes and Oneogenes" Japan Sci.Soc.Press., 8 (1990)

[Publications] Tadashi Yamamoto: "Mechanisms of Antimutagenesis Anticarcinogenesis “pp321ーpp329" Plenum Publishing Corporation, 9 (1990)

山本雅東京大学, 医科学研究所, 助教授 (40134621)

[Publications] Toshitaka Uehara: "cー<erb>_ーBー2 and cー<erb>_ーAー1 gene amphfication and cーerbBー2 protein expression in Japanese human cancers:Their relationship to the histology and diesease parameters." Jpn.J.Cancer Res.81. 620-624 (1990)