1994 Fiscal Year Annual Research Report

HTLV-Iによる細胞がん化の分子機構

Research Project

Project/Area Number	06280103
Research Institution	Tohoku University
Principal Investigator	菅村和夫東北大学, 医学部, 教授 (20117360)
Co-Investigator(Kenkyū-buntansha)	吉木敬北大, 医学部, 教授 (60220612) 内山卓京大, ウイルス研, 教授 (80151900) 藤沢順一関西医大, 教授 (40181341) 赤城剛国立がんセンター, 研究員 (90184077) 藤井雅寛金沢大, がん研, 助手 (30183099)
Keywords	ATL / HTLV-I / Tax / HAM / トランスジェニックラット / SCIDマウス
Research Abstract	HTLV-IによるT細胞腫瘍化の分子機構を明らかにするため、Taxの作用機作と動物モデルでのHTLV-I感染疾患の発症機構を解析した。Taxが、新たなNF-κBファミリー分子(p120)とPABP-1様ポリA RNA結合因子(p70)に会合していること、また、erythroid-potentiating activity遺伝子の発現を促進することを見い出した。また、SRFとの会合に必要なTaxの領域を決定した。さらに、TaxのCREBファミリーへの作用は選択的であることを認めた。Taxにより発現が促進されるIL-2受容体γ鎖に、JAK3チロシンキナーゼが会合し、JAK3はIL-2からの増殖シグナルに必須であった。Taxを正常T細胞に導入して樹立したIL-2依存性細胞株は、抗CD3抗体刺激によりチロシンリン酸化が正常細胞より亢進しており、長期培養ではCD3、Lckの発現が低下しHTLV-I感染細胞の特徴を示すようになった。SCIDマウスでの造腫瘍化能は、HTLV-I感染細胞の内、ATL由来細胞株のみにみられた。pX遺伝子導入トランスジェニックラットの乳癌に既知の乳癌関連遺伝子の変異は見られず、env-pXトランスジェニックラットは胸腺萎縮と、多くの臓器で炎症を示した。脱髄病変に先行して、局所にアポトーシスを起こしている細胞が、HAMラットに認めら、神経系で高率にTNFαが発現していた。上記のように、in vitroでもin vivoでも解析は進展した。しかし、HTLV-Iによる発がん機構の全容解明には至っていない。更なる前進が必要である。

Research Products
(31 results)

All Other

All Publications (31 results)

[Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)
[Publications] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-linked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)
[Publications] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)
[Publications] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-myc induction and cell proliferation." FEBS Letters. 351. 201-206 (1994)
[Publications] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)
[Publications] Fujii,M.: "Serum response factor has functional roles both in indirect binding to the CArG box and in the transcriptional activation function of human T-cell leukemia virus type I Tax." J.Virol.68. 7275-7283 (1994)
[Publications] Uchijima,M.: "Tax protein of HTLV-1 and -2 induce expression of the gene encoding erythroid-potentiating activity(tissu inhibitor of metalloproteinases-1:TIMP-1)." J.Biol.Chem.269. 14946-14950 (1994)
[Publications] Tsuchiya,H.: "Two distinct regions from a functional activation domain of the HTLV-1 trans-activator Tax1." Oncogene. 6. 337-340 (1994)
[Publications] Fujita,K.: "Enhancement of T cell receptor Signaling of Tumor-infiltrating Lymphocytes by Retrovirally Mediated fyn Gene Transduction." Jpn.J.Cancer.Res.85. 1073-1079 (1994)
[Publications] Akagi,T.: "Increased protein tyrosine-phosphorylation in primary T-cells transduced with Tax1 of Human T-cell leukemia virus typeI." FEBS Letters.358. 34-38 (1995)
[Publications] Hirai,H.: "Tax protein of human T-cell leulemia virus type I binds to the ankyrin motifs of inhibitory factor kB and induces nuclear translocation of transcription factor NF-kB proteins for transcriptional activation." Proc.Natl.Acad.Sci.USA.91. 3584-3588 (1994)
[Publications] Fujimoto,T.: "Novel isoforms of human cyclic AMP-responsive element modulator(hCREM)mRNA." J.Biochem.115. 298-303 (1994)
[Publications] Yamada,T.: "The HTLV-I Tax protein induces apoptosis which is blocked by the BcI-2 protein." J.Virol.68. 3374-3379 (1994)
[Publications] Inoue,H.: "Suppression of the transformed phenotype in hybrids of human T-cell leukemia virus type I Tax-transformed rat fibroblasts and normal human fibroblasts." Exp.Cell Res.215. 68-74 (1994)
[Publications] Nishimura,M.: "Demonstration of human T lymphotropic virus type I(HTLV-I)-specific T cell responses from seronegative and polymerase chain reaction-negative persons exposed to HTLV-I." J.Infect.Dis.170. 334-338 (1994)
[Publications] Uchiyama,T.: "Pathophysiology of adult T cell leukemia cells--cell growth characteristics-- In “Adult T cell leukemia"(ed.by K.Takatsuki)" Oxford University Press,Oxford. 181-203 (1994)
[Publications] Takaori-K.: "Detection fo homing,proliferation,and infiltration sites of adult Tcelleukemiacells in severe combined immunodeficiency mice using radiometric techniques." Jpn.J.Cancer Res.,in press.(1995)
[Publications] Tateno,Y.: "Genetic and functional variabilities in the human immunodeficiency virus type 1 isolated from the same blood samples with and without CD8+ cells." Immunology & Infectious Disease. 4. 41-46 (1994)
[Publications] Kitamura,M.: "Expression of an endogenous retroviral gene product in human placenta." Int.J.Cancer. 58. 836-840 (1994)
[Publications] Seto,K.: "A rat model of HTLV-I infection.Development of chronic progressive myeloneuropathy in seropositive WKAH rats and related apoptosis." Acta Neuropahol.,. (in press.).
[Publications] Takeuchi,K.: "Expression of endogenous retroviruses,ERV3 and 14-1,in synovial tissues from patients with rheumatoid arthritis." Ciln Exp.Immunol.,. (in press.).
[Publications] Sakai, R.: "A novel signaling molecule,p130,forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner." EMBOJ.13. 3748-3756 (1994)
[Publications] Sakai, R.: "Characterization and purification of p130,the main phosphoprotein associated with v-Crk oncoprotein." J.Biol.Chem.269. 32740-23746 (1994)
[Publications] Okumura,N.: "Vasoactive intestinal peptide induces differentiation and MAP kinase activation in PC12h cells." J.Biochem.115. 304-308 (1994)
[Publications] Okumura,N.: "Vasoactive intestinal peptide induces tyrosine phosphorylation in PC12th cells." J.Biochem.116. 341-345 (1994)
[Publications] Miyake,K.: "Murine B cell Proliferation and Protection from Apoptosis with an Antibody against a 105-kD Molecule:Unresponsiveness of X-linked Immunodeficient B cells." J.Exp.Med.180. 1217-1224 (1994)
[Publications] Sato,S.: "IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases." J.Exp.Med.180. 2101-2111 (1994)
[Publications] Tomida,S.: "Intercellular adhesion molecule-1 and leukocyte function-associated antigen-I are involved in protection mediated by CD3+TCRab- T cells at the early stage after infection with Listeria monocytogenes in rats." Int.Immunol.6. 955-961 (1994)
[Publications] Ohtsuka,K.: "Similarities and differences between extrathymic T cells residing in mouse liver and intestine." Cell Immunol.153. 52-66 (1994)
[Publications] Hiromatsu,K.: "Increased Fas antigen expression in murine retrovirus-induced immunodeficiency syndrome,MAIDS." Eur.J.Immunol.24. 2446-2451 (1994)
[Publications] Aoki,Y.: "Clonal expansion but lack of subsequent clonal deletion of bacterial superantigen-reactive T cells in murine retroviral infection." J.Immunol.153. 3611-3621 (1994)

1994 Fiscal Year Annual Research Report

HTLV-Iによる細胞がん化の分子機構

Principal Investigator

菅村 和夫 東北大学, 医学部, 教授 (20117360)

Research Products

[Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)

[Publications] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-linked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)

[Publications] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)

[Publications] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-myc induction and cell proliferation." FEBS Letters. 351. 201-206 (1994)

[Publications] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)

[Publications] Fujii,M.: "Serum response factor has functional roles both in indirect binding to the CArG box and in the transcriptional activation function of human T-cell leukemia virus type I Tax." J.Virol.68. 7275-7283 (1994)

[Publications] Uchijima,M.: "Tax protein of HTLV-1 and -2 induce expression of the gene encoding erythroid-potentiating activity(tissu inhibitor of metalloproteinases-1:TIMP-1)." J.Biol.Chem.269. 14946-14950 (1994)

[Publications] Tsuchiya,H.: "Two distinct regions from a functional activation domain of the HTLV-1 trans-activator Tax1." Oncogene. 6. 337-340 (1994)

[Publications] Fujita,K.: "Enhancement of T cell receptor Signaling of Tumor-infiltrating Lymphocytes by Retrovirally Mediated fyn Gene Transduction." Jpn.J.Cancer.Res.85. 1073-1079 (1994)

[Publications] Akagi,T.: "Increased protein tyrosine-phosphorylation in primary T-cells transduced with Tax1 of Human T-cell leukemia virus typeI." FEBS Letters.358. 34-38 (1995)

[Publications] Hirai,H.: "Tax protein of human T-cell leulemia virus type I binds to the ankyrin motifs of inhibitory factor kB and induces nuclear translocation of transcription factor NF-kB proteins for transcriptional activation." Proc.Natl.Acad.Sci.USA.91. 3584-3588 (1994)

[Publications] Fujimoto,T.: "Novel isoforms of human cyclic AMP-responsive element modulator(hCREM)mRNA." J.Biochem.115. 298-303 (1994)

[Publications] Yamada,T.: "The HTLV-I Tax protein induces apoptosis which is blocked by the BcI-2 protein." J.Virol.68. 3374-3379 (1994)

[Publications] Inoue,H.: "Suppression of the transformed phenotype in hybrids of human T-cell leukemia virus type I Tax-transformed rat fibroblasts and normal human fibroblasts." Exp.Cell Res.215. 68-74 (1994)

[Publications] Nishimura,M.: "Demonstration of human T lymphotropic virus type I(HTLV-I)-specific T cell responses from seronegative and polymerase chain reaction-negative persons exposed to HTLV-I." J.Infect.Dis.170. 334-338 (1994)

[Publications] Uchiyama,T.: "Pathophysiology of adult T cell leukemia cells--cell growth characteristics-- In “Adult T cell leukemia"(ed.by K.Takatsuki)" Oxford University Press,Oxford. 181-203 (1994)

[Publications] Takaori-K.: "Detection fo homing,proliferation,and infiltration sites of adult Tcelleukemiacells in severe combined immunodeficiency mice using radiometric techniques." Jpn.J.Cancer Res.,in press.(1995)

[Publications] Tateno,Y.: "Genetic and functional variabilities in the human immunodeficiency virus type 1 isolated from the same blood samples with and without CD8+ cells." Immunology & Infectious Disease. 4. 41-46 (1994)

[Publications] Kitamura,M.: "Expression of an endogenous retroviral gene product in human placenta." Int.J.Cancer. 58. 836-840 (1994)

[Publications] Seto,K.: "A rat model of HTLV-I infection.Development of chronic progressive myeloneuropathy in seropositive WKAH rats and related apoptosis." Acta Neuropahol.,. (in press.).

[Publications] Takeuchi,K.: "Expression of endogenous retroviruses,ERV3 and 14-1,in synovial tissues from patients with rheumatoid arthritis." Ciln Exp.Immunol.,. (in press.).

[Publications] Sakai, R.: "A novel signaling molecule,p130,forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner." EMBOJ.13. 3748-3756 (1994)

[Publications] Sakai, R.: "Characterization and purification of p130,the main phosphoprotein associated with v-Crk oncoprotein." J.Biol.Chem.269. 32740-23746 (1994)

[Publications] Okumura,N.: "Vasoactive intestinal peptide induces differentiation and MAP kinase activation in PC12h cells." J.Biochem.115. 304-308 (1994)

[Publications] Okumura,N.: "Vasoactive intestinal peptide induces tyrosine phosphorylation in PC12th cells." J.Biochem.116. 341-345 (1994)

[Publications] Miyake,K.: "Murine B cell Proliferation and Protection from Apoptosis with an Antibody against a 105-kD Molecule:Unresponsiveness of X-linked Immunodeficient B cells." J.Exp.Med.180. 1217-1224 (1994)

[Publications] Sato,S.: "IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases." J.Exp.Med.180. 2101-2111 (1994)

[Publications] Tomida,S.: "Intercellular adhesion molecule-1 and leukocyte function-associated antigen-I are involved in protection mediated by CD3+TCRab- T cells at the early stage after infection with Listeria monocytogenes in rats." Int.Immunol.6. 955-961 (1994)

[Publications] Ohtsuka,K.: "Similarities and differences between extrathymic T cells residing in mouse liver and intestine." Cell Immunol.153. 52-66 (1994)

[Publications] Hiromatsu,K.: "Increased Fas antigen expression in murine retrovirus-induced immunodeficiency syndrome,MAIDS." Eur.J.Immunol.24. 2446-2451 (1994)

[Publications] Aoki,Y.: "Clonal expansion but lack of subsequent clonal deletion of bacterial superantigen-reactive T cells in murine retroviral infection." J.Immunol.153. 3611-3621 (1994)

菅村和夫東北大学, 医学部, 教授 (20117360)