1991 Fiscal Year Annual Research Report

HTLVーI感染細胞の増殖癌化の分子機構

Research Project

Project/Area Number	03151006
Research Institution	Tohoku University
Principal Investigator	菅村和夫東北大学, 医学部, 教授 (20117360)
Co-Investigator(Kenkyū-buntansha)	淀井淳司京都大学, ウイルス研究所, 教授 (80108993) 丹生谷博国立がんセンター研究所, 主任研究官 (60135936) 野阪哲哉京都大学, ウイルス研究所, 助手 (30218309) 清木元治金沢大学, がん研究所, 教授 (10154634) 藤沢順一東京大学, 医科学研究所, 助手 (40181341)
Keywords	HTLVーI / ATL / p40^<tax> / 転写促進因子 / 機能ドメイン / p27^<rex> / HTLVーIキャリア-ラット
Research Abstract	HTLVーIによる細胞癌化の分子機構の中で、初期過程で重要と考えられているp40^<tax>の転写促進作用の解析が進んでいる。HTLVーI・LTR上の21塩基配列を介する経路とNFーκB結合配列を介する経路の2種類の異なる転写経路をp40^<tax>が活性化することが知られているが、それぞれに作用する機能ドメインがp40^<tax>上で異なることが明らかにされた。さらにこれらの活性化には細胞性因子が関与することが証明された。このp40^<tax>の活性化に関与する細胞性因子の一つで、21塩基配列に結合するTRFB因子はリン酸化によって、その結合が制御されていることが明らかとなった。ADF因子がNFーκB結合配列に結合する細胞性因子の結合量を増大させることを示した。さらに、p40^<tax>の転写活性促進機能ドメインは、他の転写活性化因子の機能ドメインと置換可能であることが示された。これらp40^<tax>の転写促進系に関与する個々の因子を解析するために、p40^<tax>に依存したin vitro転写系を確立した。従来のLTR中にプラモ-タ-活性に加え、構造遺伝子内部にもプロモ-タ-活性を示す領域があることを示した。p40^<tax>の抗体に加え、p27^<rex>に対する単クロン抗体を作製し、p27^<rex>,p21の解析をさらに進めることができるようになった。p40^<tax>を発現型レトロウイルスベクタ-に組み込み、これを正常末梢血T細胞に導入することによって、ILー2依存性細胞株を得ることに成功した。また、p40^<tax>によりトランスフォ-ムした細胞を変異原処理して得られた正常復帰細胞株はすべてp40^<tax>の12番目のアミノ酸が変異していた。HTLVーI感染の動物モデルとなるHTLVーI持続感染ラットを作出し、動物実験におけるHTLVーI免疫応答を解析した。さらにp40^<tax>のトランスジェニックマウスを作成した。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Miura,s.: "Molecular cloning and characterization of a novel glycoprotein ,gp34 that is specifically induced by the human T-cell leukemia virus type I transactivator P40^<tax>" Mol.Cell.Biol.11. 1313-1325 (1991)
[Publications] Numata,N.: "Synergism between two distrinct elements of the HTLV-I enhancer in activation by the transactivator of HTLV-I" New Biologist. 3. 896-906 (1991)
[Publications] Nagata,K.: "Complex formation of human T-cell leukemia virus type I p40^<tax> transactivator with cellular polypeptides" J.Virol.66. 1040-1049 (1992)
[Publications] Fujuisawa,J.: "The indirect association of human T-cell leuekmia virus tax protein wth DNA results in transcriptional activation" J.Virol.65. 4525-4528 (1991)
[Publications] Maekawa,T.: "CRE-binding protein,CRE-BP1,mediates the E1A-induced byt not the tax-induced trans-activation" Oncogenes. 6. 627-632 (1991)
[Publications] Fujii,M.: "HTLV-1 tax induces expression of various immediate early serum responsive genes" Oncogenes. 6. 1023-1029 (1991)
[Publications] Fujii,M.: "HTLV-1 has distinct but overlapping domains for transcriptional activation and for enhancer specificity" Oncognees. 6. 2349-2352 (1991)
[Publications] Kubota,S.: "Effects of chimeric mutants of human immunodeficiency virus type I Rev and human T-cell luekemia virus type I Rex on nucleolar targeting signals" J.Virol.65. 2452-2456 (1991)
[Publications] White,K.N.: "The nucleolar localisation signal of the HTLVーI protein p27^<rex> is important for stabilisation of ILー2 receptor α subunit mRNA by p27^<rex>" Biochem.Biophys.Res.Commun.175. 98-103 (1991)
[Publications] Kubota,S.: "Functional conversion from HIV-1 Rex to HTLV-1 Rex by mutation" Biochem.Biophys.Res.Commun.178. 1226-1232 (1991)
[Publications] Tujumoto,T.: "Isolation of cDNAs for DNA-binding proteins which specifically bind for a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I" J.Virol.65. 1420-1426 (1991)
[Publications] Akagi,T.: "Murine retroviral vectors expressing the taxl gene of human T-cell leukemia virus type 1" Gene. 106. 255-259 (1991)
[Publications] Tanaka,Y.: "An antigenic structure of trans-activator protein encoded by human T cell leukemia virus type I (HTLV-I),as defined by a panel of monoclonal antibodies" AIDS & Human Retroviruses. 8. 227-235 (1992)
[Publications] Tanaka,Y.: "Immunogenicity of human T cell leukemia virus type I (HTLV-I)antigens for cytotoxic T lymphocytes in the rat system" J.Immunol.147. 3646-3652 (1991)
[Publications] Tanaka,Y.: "Production of a recombinant human T cell leukemia virus type-I transactivator (taxl) antigen and its utilization for generation of monoclonal antibodies against various epitopes on the taxl antigen" Int.J.Cancer. 48. 623-630 (1991)
[Publications] Tanaka,Y.: "Identification of a neutralization epitope on the envelope gp46 antigen of human T cell leuekmia virus type I and induction of neutralizing antibody by peptide immunization" J.Immunol.147. 354-360 (1991)
[Publications] Fujii,S.: "Coexpression of adult T-cell leukemia-derived factor,a human thioredoxin homologue,and human papillomavirus DNA in neoplastic cervical squamous epithelium" Cancer. 68. 1583-1591 (1991)
[Publications] Yoshiki,T.: "A rat model of HTLV-I infection" Gann Monograph. 39. (1991)

1991 Fiscal Year Annual Research Report

HTLVーI感染細胞の増殖癌化の分子機構

Principal Investigator

菅村 和夫 東北大学, 医学部, 教授 (20117360)

Research Products

[Publications] Miura,s.: "Molecular cloning and characterization of a novel glycoprotein ,gp34 that is specifically induced by the human T-cell leukemia virus type I transactivator P40^<tax>" Mol.Cell.Biol.11. 1313-1325 (1991)

[Publications] Numata,N.: "Synergism between two distrinct elements of the HTLV-I enhancer in activation by the transactivator of HTLV-I" New Biologist. 3. 896-906 (1991)

[Publications] Nagata,K.: "Complex formation of human T-cell leukemia virus type I p40^<tax> transactivator with cellular polypeptides" J.Virol.66. 1040-1049 (1992)

[Publications] Fujuisawa,J.: "The indirect association of human T-cell leuekmia virus tax protein wth DNA results in transcriptional activation" J.Virol.65. 4525-4528 (1991)

[Publications] Maekawa,T.: "CRE-binding protein,CRE-BP1,mediates the E1A-induced byt not the tax-induced trans-activation" Oncogenes. 6. 627-632 (1991)

[Publications] Fujii,M.: "HTLV-1 tax induces expression of various immediate early serum responsive genes" Oncogenes. 6. 1023-1029 (1991)

[Publications] Fujii,M.: "HTLV-1 has distinct but overlapping domains for transcriptional activation and for enhancer specificity" Oncognees. 6. 2349-2352 (1991)

[Publications] Kubota,S.: "Effects of chimeric mutants of human immunodeficiency virus type I Rev and human T-cell luekemia virus type I Rex on nucleolar targeting signals" J.Virol.65. 2452-2456 (1991)

[Publications] White,K.N.: "The nucleolar localisation signal of the HTLVーI protein p27^<rex> is important for stabilisation of ILー2 receptor α subunit mRNA by p27^<rex>" Biochem.Biophys.Res.Commun.175. 98-103 (1991)

[Publications] Kubota,S.: "Functional conversion from HIV-1 Rex to HTLV-1 Rex by mutation" Biochem.Biophys.Res.Commun.178. 1226-1232 (1991)

[Publications] Tujumoto,T.: "Isolation of cDNAs for DNA-binding proteins which specifically bind for a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I" J.Virol.65. 1420-1426 (1991)

[Publications] Akagi,T.: "Murine retroviral vectors expressing the taxl gene of human T-cell leukemia virus type 1" Gene. 106. 255-259 (1991)

[Publications] Tanaka,Y.: "An antigenic structure of trans-activator protein encoded by human T cell leukemia virus type I (HTLV-I),as defined by a panel of monoclonal antibodies" AIDS & Human Retroviruses. 8. 227-235 (1992)

[Publications] Tanaka,Y.: "Immunogenicity of human T cell leukemia virus type I (HTLV-I)antigens for cytotoxic T lymphocytes in the rat system" J.Immunol.147. 3646-3652 (1991)

[Publications] Tanaka,Y.: "Production of a recombinant human T cell leukemia virus type-I transactivator (taxl) antigen and its utilization for generation of monoclonal antibodies against various epitopes on the taxl antigen" Int.J.Cancer. 48. 623-630 (1991)

[Publications] Tanaka,Y.: "Identification of a neutralization epitope on the envelope gp46 antigen of human T cell leuekmia virus type I and induction of neutralizing antibody by peptide immunization" J.Immunol.147. 354-360 (1991)

[Publications] Fujii,S.: "Coexpression of adult T-cell leukemia-derived factor,a human thioredoxin homologue,and human papillomavirus DNA in neoplastic cervical squamous epithelium" Cancer. 68. 1583-1591 (1991)

[Publications] Yoshiki,T.: "A rat model of HTLV-I infection" Gann Monograph. 39. (1991)

菅村和夫東北大学, 医学部, 教授 (20117360)