Human T-cell leukemia virus type 1 Tax releases cell cycle arrest induced by p16INK4a
Human T-cell leukemia virus type 1 Tax releases cell cycle arrest induced by p16INK4a
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DOI：
10.1128/jvi.71.3.1956-1962.1997
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发表时间：
1997-03
影响因子：
5.4
通讯作者：
Kenneth G. Low;Lydia F. Dorner;Dinali B. Fernando;Joseph Grossman;K. Jeang;Michael J. Comb
中科院分区：
文献类型：
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作者：
Kenneth G. Low;Lydia F. Dorner;Dinali B. Fernando;Joseph Grossman;K. Jeang;Michael J. Comb
人类 T 细胞白血病病毒 1 型 (HTLV-1) Tax 癌蛋白通过解除对 DNA 修复、转录、信号转导、增殖和生长等重要细胞过程的调节来引起细胞转化。尽管很明显正常细胞周期控制在 HTLV-1 诱导的细胞转化过程中失调，但 Tax 对细胞周期控制的影响尚不清楚。对人类 T 细胞的流式细胞术分析表明，Tax 可以缓解 p16INK4a 在 G1 晚期、G1/S 限制点或之前的细胞周期停滞。此外，5-溴-2'-脱氧尿苷掺入和转录激活的Tax依赖性刺激被p16INK4a抑制。这一结果表明 p16INK4a 能够阻断 DNA 合成和细胞周期进展至 S 期的税务依赖性刺激。重组谷胱甘肽 S-转移酶融合蛋白和 [35S] 蛋氨酸标记蛋白的体外结合测定表明，Tax 与 p16INK4a 特异性结合，但不与 p21cip1 或 p27kip1 结合。此外，在与Tax和p16INK4a共表达后，用特异性抗血清和[35S]甲硫氨酸标记的细胞裂解物进行连续免疫沉淀测定表明这两种蛋白在体内形成复合物。使用细胞周期蛋白依赖性激酶 4 抗血清进行的免疫复合物激酶测定表明，Tax 可阻断 p16INK4a 对 cdk4 激酶活性的抑制。这项研究将 p16INK4a 确定为 Tax 的新细胞靶标，并表明 p16INK4a 功能失活是 Tax 细胞周期失调的机制。
The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein causes cellular transformation by deregulating important cellular processes such as DNA repair, transcription, signal transduction, proliferation, and growth. Although it is clear that normal cell cycle control is deregulated during HTLV-1-induced cellular transformation, the effects of Tax on cell cycle control are not well understood. Flow cytometric analyses of human T cells indicate that cell cycle arrest in late G1, at or before the G1/S restriction point, by p16INK4a is relieved by Tax. Furthermore, Tax-dependent stimulation of 5-bromo-2'-deoxyuridine incorporation and transcriptional activation is inhibited by p16INK4a. This result suggests that p16INK4a is able to block Tax-dependent stimulation of DNA synthesis and cell cycle progression into S phase. In vitro binding assays with recombinant glutathione S-transferase fusion proteins and [35S]methionine-labeled proteins indicate that Tax binds specifically with p16INK4a but not with either p21cip1 or p27kip1. Furthermore, sequential immunoprecipitation assays with specific antisera and [35S]methionine-labeled cell lysates subsequent to coexpression with Tax and p16INK4a indicate that the two proteins form complexes in vivo. Immunocomplex kinase assays with cyclin-dependent kinase 4 antiserum indicate that Tax blocks the inhibition of cdk4 kinase activity by p16INK4a. This study identifies p16INK4a as a novel cellular target for Tax and suggests that the inactivation of p16INK4a function is a mechanism of cell cycle deregulation by Tax.