Molecular basis on E2F acitivation by HTLV-I Tax

HTLV-I Tax 激活 E2F 的分子基础

• 批准号: 11138223
• 负责人: NAKAMURA Masataka
• 金额: $ 6.4万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11138223/
• 关键词: HTLV-I; Tax; E2F; cell cycle; DNA sythesis; T cell; HTLV-1

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.

人T细胞白血病病毒Ⅰ型（HTLV-Ⅰ）的反式激活蛋白Tax在成人T细胞白血病的发生发展中起重要作用。已经表明Tax调节许多生长调节分子和基因（包括p16）的表达和活性<INK4a>。然而，Tax诱导白血病发生的分子机制尚未阐明。我们先前已经证明Tax以细胞类型依赖性和p16^<INK4a>-非依赖性的方式激活IL-2饥饿的Kit 225细胞中的内源性E2 F活性，该细胞可以通过剥夺IL-2而在G 0/G1期经历细胞周期停滞。Tax突变体激活E2 F的能力与激活NF-κB和NF-AT的能力一致，但NF-AT的单独表达并不能激活E2 F，提示Tax的激活可能通过另一条途径。类似地，用植物血凝素预刺激的外周血细胞观察到Tax诱导的细胞周期进展。对Tax突变体的分析不能将Tax诱导的细胞周期进程与Tax依赖的E2 F激活区分开来，这表明Tax可能通过激活E2 F来诱导细胞周期进程。对于IL-2饥饿的Kit 225细胞中的E2 F活化或细胞周期进程，Tax不充分，这意味着Tax活化的T细胞中的E2 F活化和细胞周期进程的差异调节。Tax诱导Kit 225细胞G 0/G1期E2 F阻遏蛋白p130的磷酸化和降解。

项目成果

Nagata,K.: "Selective expression of a novel G protein-coupled receptor by human T helper 2 cells." J.Immunol.162. 1278-1286 (1999)

Nagata,K.：“人类 T 辅助 2 细胞选择性表达新型 G 蛋白偶联受体。”

Tanaka, K.: "Differential production of prostaglandin D2 by human helper T cell subsets."J. Immunol.. (in press). (2000)

Tanaka, K.：“人类辅助 T 细胞亚群产生前列腺素 D2 的差异。”J.

Tsukahara,T.: "Induction of Bcl-X_L expression by HTLV-I Tax through NF-κB in apoptosis-resistant T-cel transformants with Tax."J.Virol.. 73. 7981-7987 (1999)

Tsukahara, T.：“HTLV-I Tax 通过 NF-κB 在具有 Tax 的抗凋亡 T 细胞转化体中诱导 Bcl-X_L 表达。J. Virol.. 73. 7981-7987 (1999)

Tsukahara,T.: "Induction of Bcl-XL expression by HTLV-I Tax through NF-κB in apoptosis-resistant T-cell transformants with Tax."J.Virol.. 73. 7981-7987 (1999)

Tsukahara, T.：“HTLV-I Tax 通过 NF-κB 在具有 Tax 的抗凋亡 T 细胞转化体中诱导 Bcl-XL 表达。J. Virol.. 73. 7981-7987 (1999)

Ohtani,K.: "Cell type-specitic E2F activation cell cycle progression by the oncogene product Tax of human T-cell leukemia virus type I."J.Biol.Chem.. (In press). (2000)

Ohtani,K.：“人类 T 细胞白血病病毒 I 型的癌基因产物 Tax 导致细胞类型特异性 E2F 激活细胞周期进程。”J.Biol.Chem..（正在出版）。