1992 年度実績報告書

HTLV-I感染細胞の増殖癌化の分子機構

研究課題

研究課題/領域番号	04151006
研究機関	東北大学
研究代表者	菅村和夫東北大学, 医学部, 教授 (20117360)
研究分担者	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, 主住研究官 (60135936) 野阪哲也京都大学, 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)
キーワード	ATL / HAM / HTLV-I / p40^<tax> / HILV-I感染ラット
研究概要	細胞癌化に重要な役割を果たしているHTLV-Iのトランスアクチベーターp40^<tax>の作用機作の解析が進んだ。p40^<tax>はc-fos,egr-1,2等の細胞性初期遺伝子群の発現を増強することをすでに示した。この作用はCArGボックスを介して誘導される。p40^<tax>はCArGボックスに直接結合するSRFと直接結合し、SRFの転写活性化能に影響を与える。転写活性化にかかわる領域に変異があるp40^<tax>はSRFとの結合能は保持していても、SRFを活性化できない。この変異はVP16の転写活性化領域と置換可能である。p40^<tax>はCREB,CREMとも結合し、この複合体がHTLV-I LTRの21bpエンハンサーに結合する。また、HUT102細胞の核抽出液中の21bp,NF-κB配列各々に結合活性を持つ分画にはin-vitroでエンハンサー特異的な転写活性能を認めたが、p40^<tax>のみの分画には転写性化は認められなかった。これらの知見により、p40^<tax>はエンハンサーに直接結合する因子と基本転写因子の架け橋の役割を果たしている可能性が考えられる。HTLV-I感染ラットがHAM様症状を呈した。HTLV-I産生細胞株であるMT-2をWKAラットに静注することにより、HTLV-I持続感染ラットができる。感染後1年以上後に前後肢の痙性麻痺等のHAM様症状を呈した。病理所見にて、下部胸髄の後索、側索を中心に変性が認められ、マクロファージ等の細胞浸潤も見られた。他の系統ラットのHTLV-I持続感染ラットではHAM様症状は見られず、発症には遺伝的素因の関与の可能性がある。HTLV-I感染細胞に持続的に発現する高親和性IL-2受容体は従来のα鎖β鎖サブユニットに加えγ鎖が必須であることを明らかにし、γ鎖遺伝子のクローニングに成功した。γ鎖はサイトカイン受容体ファミリーに属しIL-2による細胞増殖の情報伝達に不可欠の分子である。

研究成果
(25件)

すべてその他

すべて文献書誌 (25件)

[文献書誌] Nagata,K.: "Complex formation of human T-cell leukemia virus type I p40^<tax> transactivator with cellular polypeptides." J.Virol.66. 1040-1049 (1992)
[文献書誌] Sugamura,K.: "Expression of IL-2 receptor subunits,α,β and γ,on HTLV-I-transformed T cells." Gann Monograph on Cancer Research. 39. 119-128 (1992)
[文献書誌] Niki,M.: "Multistep regulation of enhancer activity of the 21-base-pair element of human T-cell leukemia virus type I." J.Virol.66. 4348-4357 (1992)
[文献書誌] Takeshita, T.: "Cloning of the γ chain of the human IL-2 receptor." Science. 257. 379-382 (1992)
[文献書誌] Adachi,Y.: "Expression of calpain II gene in human hematopoietic system cells infected with human T-cell leukemia virus type I." J.Biol.Chem.267. 19373-19378 (1992)
[文献書誌] Fujisawa,J.: "The indirect association of human T-cell leukemia virus tax protein with DNA results in transcriptional activation." J.Virol.65. 4525-4528 (1991)
[文献書誌] Maekawa,T.: "CRE-binding protein,CRE-BPI,mediates the ELA-induced but not the tax-induced transamtivation." Oncogene. 6. 627-632 (1991)
[文献書誌] Aoyama,N.: "overlap of the P53-responsive element and cAMP-responsive element in the enhancer of human T-cell leukemia virus type I." Proc.Natl.Acad.Sci.USA. 89. 5403-5407 (1992)
[文献書誌] Hirai,H.: "Transcriptional activator Tax of HTLV-I binds to the NF-XB precursor p105." Oncogene. 7. 1737-1742 (1992)
[文献書誌] Uchiume,F.: "Characterization of the promoter region of the src family gene lyn and its trans activation by huma T-cell leukemia virus type I-encoded p40^<tax>." Mol.Cell.Biol.12. 3784-3795 (1992)
[文献書誌] Yamashita,K.: "Evaluation of enzyme immunoassay using a recombinant envelope protein expressed in insect cells for serelogical confixmation of HTLV-I infection." AIDS Res.Human Retroviruses. 8. 1857-1861 (1992)
[文献書誌] Tanaka,Y.: "An antigenic structure of the trans-activator protein encoded by human T-cell leukemia virus type-I(HTLV-I),as defined by panel of monoclonal antibodies." AIDS Res.Human Retroviruses. 8. 227-235 (1992)
[文献書誌] Fujii,M.: "Interaction of HTLV-I Tax 1 with p67^<SRF> causes the aberrant induction of cellular immediate early genes through CArG boxes." Genes and Development. 6. 2066-2076 (1992)
[文献書誌] Sakurai,M.: "Transforming activity and the level of Tax protein:Effect of one point mutation in HTLV-I tax gane." Int.J.Cancer. 52. 323-328 (1992)
[文献書誌] Adachi,Y.: "Phosphorylation of the Rex protein of human T-cell leukemia virus type I." J.Biol.Chem.267. 21977-21981 (1992)
[文献書誌] Setoyama,M.: "Expression of human T-cell lymphotropic verus type-I gene products in the short-term cultured skin tissues of an adult T-cell leukemia/lymphoma patient with cutaneous manifestations." J.Dermatology. 19. 133-139 (1992)
[文献書誌] Makino,S.: "Adult T cell leukemia derived factor (ADF)/Thioredoxin ecpression on the HTLV-I transformed T cell lines:Hmterogeneous ixpression in ATL-2 cells." Immunology. 76. 578-583 (1992)
[文献書誌] Mitsui,A.: "Reactive oxygen-reducing and proteinrefolding activities of adult T cell leukemia-derived factor/human thioredoxin." Biochem.Biophys.Res.Commun.186. 1220-1226 (1992)
[文献書誌] Yodoi,J.: "Diseases associated with HTLV-I:Virus,IL-2 receptor dysregulation and redox regulation." Immunology Today. 13. 405-411 (1992)
[文献書誌] Uchiyama,T.: "Interleukin-2 receptor α chain expression in ATL." Gann Monograph. 39. 107-118 (1992)
[文献書誌] Yoshiki,T.: "A Rat Model of HTLV-I Infection." Gann Monograph on Cancer Res.39. 205-216 (1992)
[文献書誌] Sakurai,H.: "Case report,molecular analysis of a HTLV-I px defective human adult T-cell leukemia." Leukemia Res.16. 941-989 (1992)
[文献書誌] Ishiguro,N.: "A rat model of HTLV-I infection. I. Humoral antibody response,provirus integration and HAM/TSP-like myelopathy in seronegative HTLV-I carrier rats." J.Exp.Med.176. 981-989 (1992)
[文献書誌] Oka,T.: "Phenotypic progfession of a rat lymphoid cell line immortalized by huma T-lymphotropic virus type I to induce lymphona/leukemia-like disease in rats." J.Virol.66. 6686-6694 (1992)
[文献書誌] Kuraya,M.: "CD21 a B lymphocyte marker,is strongly expressed and exhibits its functional characteristics on the HTLV-I T cell line MT-2."

1992 年度 実績報告書

HTLV-I感染細胞の増殖癌化の分子機構

研究代表者

菅村 和夫 東北大学, 医学部, 教授 (20117360)

研究成果

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

[文献書誌] Sugamura,K.: "Expression of IL-2 receptor subunits,α,β and γ,on HTLV-I-transformed T cells." Gann Monograph on Cancer Research. 39. 119-128 (1992)

[文献書誌] Niki,M.: "Multistep regulation of enhancer activity of the 21-base-pair element of human T-cell leukemia virus type I." J.Virol.66. 4348-4357 (1992)

[文献書誌] Takeshita, T.: "Cloning of the γ chain of the human IL-2 receptor." Science. 257. 379-382 (1992)

[文献書誌] Adachi,Y.: "Expression of calpain II gene in human hematopoietic system cells infected with human T-cell leukemia virus type I." J.Biol.Chem.267. 19373-19378 (1992)

[文献書誌] Fujisawa,J.: "The indirect association of human T-cell leukemia virus tax protein with DNA results in transcriptional activation." J.Virol.65. 4525-4528 (1991)

[文献書誌] Maekawa,T.: "CRE-binding protein,CRE-BPI,mediates the ELA-induced but not the tax-induced transamtivation." Oncogene. 6. 627-632 (1991)

[文献書誌] Aoyama,N.: "overlap of the P53-responsive element and cAMP-responsive element in the enhancer of human T-cell leukemia virus type I." Proc.Natl.Acad.Sci.USA. 89. 5403-5407 (1992)

[文献書誌] Hirai,H.: "Transcriptional activator Tax of HTLV-I binds to the NF-XB precursor p105." Oncogene. 7. 1737-1742 (1992)

[文献書誌] Uchiume,F.: "Characterization of the promoter region of the src family gene lyn and its trans activation by huma T-cell leukemia virus type I-encoded p40^<tax>." Mol.Cell.Biol.12. 3784-3795 (1992)

[文献書誌] Yamashita,K.: "Evaluation of enzyme immunoassay using a recombinant envelope protein expressed in insect cells for serelogical confixmation of HTLV-I infection." AIDS Res.Human Retroviruses. 8. 1857-1861 (1992)

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

[文献書誌] Fujii,M.: "Interaction of HTLV-I Tax 1 with p67^<SRF> causes the aberrant induction of cellular immediate early genes through CArG boxes." Genes and Development. 6. 2066-2076 (1992)

[文献書誌] Sakurai,M.: "Transforming activity and the level of Tax protein:Effect of one point mutation in HTLV-I tax gane." Int.J.Cancer. 52. 323-328 (1992)

[文献書誌] Adachi,Y.: "Phosphorylation of the Rex protein of human T-cell leukemia virus type I." J.Biol.Chem.267. 21977-21981 (1992)

[文献書誌] Setoyama,M.: "Expression of human T-cell lymphotropic verus type-I gene products in the short-term cultured skin tissues of an adult T-cell leukemia/lymphoma patient with cutaneous manifestations." J.Dermatology. 19. 133-139 (1992)

[文献書誌] Makino,S.: "Adult T cell leukemia derived factor (ADF)/Thioredoxin ecpression on the HTLV-I transformed T cell lines:Hmterogeneous ixpression in ATL-2 cells." Immunology. 76. 578-583 (1992)

[文献書誌] Mitsui,A.: "Reactive oxygen-reducing and proteinrefolding activities of adult T cell leukemia-derived factor/human thioredoxin." Biochem.Biophys.Res.Commun.186. 1220-1226 (1992)

[文献書誌] Yodoi,J.: "Diseases associated with HTLV-I:Virus,IL-2 receptor dysregulation and redox regulation." Immunology Today. 13. 405-411 (1992)

[文献書誌] Uchiyama,T.: "Interleukin-2 receptor α chain expression in ATL." Gann Monograph. 39. 107-118 (1992)

[文献書誌] Yoshiki,T.: "A Rat Model of HTLV-I Infection." Gann Monograph on Cancer Res.39. 205-216 (1992)

[文献書誌] Sakurai,H.: "Case report,molecular analysis of a HTLV-I px defective human adult T-cell leukemia." Leukemia Res.16. 941-989 (1992)

[文献書誌] Ishiguro,N.: "A rat model of HTLV-I infection. I. Humoral antibody response,provirus integration and HAM/TSP-like myelopathy in seronegative HTLV-I carrier rats." J.Exp.Med.176. 981-989 (1992)

[文献書誌] Oka,T.: "Phenotypic progfession of a rat lymphoid cell line immortalized by huma T-lymphotropic virus type I to induce lymphona/leukemia-like disease in rats." J.Virol.66. 6686-6694 (1992)

[文献書誌] Kuraya,M.: "CD21 a B lymphocyte marker,is strongly expressed and exhibits its functional characteristics on the HTLV-I T cell line MT-2."

1992 年度実績報告書

菅村和夫東北大学, 医学部, 教授 (20117360)