| 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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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 1999: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Keywords | HTLV-I / Tax / E2F / cell cycle / DNA sythesis / T cell / HTLV-1 |
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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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