2000 Fiscal Year Final Research Report Summary
Molecular basis on E2F acitivation by HTLV-I Tax
| Project/Area Number |
11138223
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas (A)
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| Allocation Type | Single-year Grants |
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
NAKAMURA Masataka Tokyo Medical and Dental University, Human Gene Sciences Center, Professor, 疾患遺伝子実験センター, 教授 (30180392)
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| Co-Investigator(Kenkyū-buntansha) |
OHTANI Kiyoshi Tokyo Medical and Dental University, Human Gene Sciences Center, Lecturer, 疾患遺伝子実験センター, 講師 (30201974)
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| Project Period (FY) |
1999
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| Keywords | HTLV-I / Tax / E2F / cell cycle / DNA sythesis / T cell |
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| Research Abstract |
The transactivator protein Tax of human T-cell leukemia virus type I (HTLV-I) plays an important role in the development of adult T-cell leukemia. It has been shown that Tax modulates expression and activity of many of growth regulatory molecules and genes including p16^<INK4a>. The molecular mechanism of leukemogenesis induced by Tax is yet to be elucidated, however. We have previously shown that Tax activated endogenous E2F activity in a cell type-dependent and p16^<INK4a> -independent manner in IL-2 starved Kit 225 cells, which can undergo cell cycle arrest at G0/G1 phase by deprivation of IL-2. The ability of Tax mutants to activate E2F coincided with that to activate NF-κB and NF-AT sole expression of which, however, did not activate E2F, suggesting involvement of another pathway in activation of E2F.Introduction of Tax by a recombinant adenovirus induced cell cycle progression to G2/M phase in resting Kit 225 cells accompanied by endogenous cyclin D2 gene expression. Similarly Tax-induced cell cycle progression was seen with peripheral blood cells prestimulated with phytohemagglutinin. Analyses with Tax mutants did not allow Tax-induced cell cycle progression to be differentiated from Tax-dependent activation of E2F, suggesting that Tax induces cell cycle progression presumably through activation of E2F.Nevertheless, infection with an E2F1 expressing virus, which is sufficient for induction of S phase in serum starved fibroblasts, was not stufficient for either E2F activation or cell cycle progression in IL-2 starved Kit 225 cells, implying differential regulation of E2F activation and cell cycle progression in T cells that is activated by Tax. Tax induced phosphorylation and degradation of p130, a repressor of E2F at G0/G1 phase of Kit225 cells.
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[Publications] Nagata, K., Tanaka, K., Ogawa, K., Kemmotsu, K., Imai, T., Yoshie, O., Abe, H., Tada, K., Nakamura, M., Sugamura, K & Takano, S.: "Selective expression of a novel G protein-coupled receptor by human T helper 2 cells."J.Immunol.. 162. 1278-1286 (1999)
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[Publications] Iwanaga, Y., Tsukahara, T., Ohashi, T., Tanaka, Y., Arai, M., Nakamura, M., Ohtani, K., Koya, Y., Kannagi, M., Yamamoto, N.& Fujii, M.: "Human T -cell leukemia virus type I Tax protein abrogates interleukin 2-dependence in a mouse T -cell line."J.Virol.. 73. 1271-1277 (1999)
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[Publications] Ohtani, K., Iwanaga, R., Nakamura, M., Ikeda, M., Yubata, N., Tsuruga, H.& Nojima, H.: "Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F."Oncogene. 18. 2299-2309 (1999)
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[Publications] Ohteki, T., Fukao, T., Suzue, K., Maki, C., Ito, M., Nakamura, M.& Koyasu, S.: "Interleukin-12 dependent interferon-γ production by CD8α^+ lymphoid dendric cells."J.Exp. Med.. 189. 1981-1986 (1999)
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[Publications] Tsukahara, T., Kannnagi, M., Ohashi, T., Kato, H., Arai, M., Nunez, G., Iwanaga, Y., Yamamoto, N., Ohtani, K., Nakamura, M.& Fujii, M.: "Induction of Bcl-X_L expression by HTLV-I Tax through NF-κB in apoptosis-resistant T -cell transformants with Tax."J.Virol.. 73. 7981-7987 (1999)
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[Publications] Nagata, K., Hirai, H., Tanaka, K., Ogawa, K., Aso, T., Sugamura, K., Nakamura, M.& Takano, S.: "CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s)."FEBS Letters. 459. 195-199 (1999)
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[Publications] Tanaka, K., Ogawa, K., Sugamura, K., Nakamura, M., Takano, S.& Nagata, K.: "Differential production of prostaglandin D2 by human helper T cell subsets."J.Immunol.. (In press). (2000)
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[Publications] Ohtani, K., Iwanaga, R., Arai, M., Huang, Y-P., Matsumura, Y.& Nakamura, M.: "Cell type-specific E2F activation cell cycle progression by the oncogene product Tax of human T-cell leukemia virus type I."J.Biol.Chem.. (In press). (2000)
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