Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I
Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I
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DOI：
10.1074/jbc.275.15.11154
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发表时间：
2000-04-14
影响因子：
4.8
通讯作者：
Nakamura, M
中科院分区：
文献类型：
--
作者：
Ohtani, K;Iwanaga, R;Nakamura, M
人T细胞白血病病毒I型反式激活蛋白TAX可能通过调节包括p16(INK4a)在内的生长调节分子在成人T细胞白血病的发生发展中发挥重要作用。紫杉醇诱导白血病发生的分子机制尚不清楚。我们使用依赖白介素2(IL-2)的人T细胞系(Kit 225)分析了细胞周期中的Tax功能，该T细胞系可以通过剥夺IL-2而使细胞周期停滞在G(0)/G(1)期。在EL-2饥饿的Kit225细胞中，Tax激活了内源性E2F活性，导致E2F位点携带启动子的激活，参与G(1)向S相变的基因以一种细胞类型依赖和p16(INK4a)非依赖的方式转变，Tax突变体激活E2F的能力与激活核因子KB和AT的能力一致，但单独表达这两种核因子并不激活E2F，提示另一条途径参与了E2F的激活，重组腺病毒引入Tax诱导细胞周期进入G(2)/M期，伴随着内源性Cyclin D2基因的表达。TAX诱导的细胞周期进展与植物血凝素预刺激的外周血淋巴细胞有关，与TAX突变体的分析不允许将TAX诱导的细胞周期进展与税收依赖的E2F激活区分开来，这表明TAX可能通过激活E2F而诱导细胞周期进展。然而，感染表达E2F1的病毒，足以诱导血清饥饿的成纤维细胞的S期，并不足以刺激IL-2饥饿的Kit225细胞的E2F激活或细胞周期进展，这意味着在被Tax激活的T细胞中，E2F激活和细胞周期进展的调节是不同的。
The transactivator protein Tax of human T-cell leukemia virus type I plays an important role in the development of adult T-cell leukemia probably through modulation of growth regulatory molecules including p16(INK4a). The molecular mechanism of leukemogenesis induced by Tax has yet to be elucidated. We analyzed Tax function in the cell cycle using an interleukin-2 (IL-2)-dependent human T-cell line (Kit 225) that can undergo cell cycle arrest at G(0)/G(1) phase by deprivation of IL-2. Tax activated endogenous E2F activity in EL-2-starved Kit 225 cells, resulting in activation of E2F site-carrying promoters of genes involved in G(1) to S phase transition in a cell type-dependent and p16(INK4a)-independent manner, The ability of Tax mutants to activate E2F coincided with that to activate nuclear factors KB and 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 G(2)/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 lymphocytes 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 sufficient 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.