Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain
Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain
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DOI：
10.1128/jvi.72.11.8852-8860.1998
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发表时间：
1998-11-01
影响因子：
5.4
通讯作者：
Franchini, G
中科院分区：
文献类型：
--
作者：
Mulloy, JC;Kislyakova, T;Franchini, G
人类 T 细胞嗜淋巴细胞/白血病病毒 1 型 (HTLV-1) 在体外转化人类 T 细胞，Tax 是一种病毒和细胞基因的专利反式激活因子，在细胞永生化中发挥着关键作用。Tax 活性是通过与细胞转录因子（包括 CREB/ATF 家族成员、NF-kappa B/c-Rel 家族成员、血清反应因子和共激活因子 CREB 结合蛋白-p300）相互作用介导的。虽然p53在HTLV-1感染的T细胞中通常不会突变，但其半衰期延长且功能受损。在此，我们报道p53和Tax的瞬时共表达导致p53转录活性的抑制。 Tax 的表达消除了 Calu-6 细胞系中 p53 诱导的 G(1) 停滞，并防止 HeLa/Tat 细胞系中过表达 p53 诱导的细胞凋亡。 Tax 突变体 M22 和 G148V 选择性激活 CREB/ATF 途径，对 p53 功能产生相同的生物学效应。相比之下，NF-kappa B 活性 Tax 突变体 M47 对这些系统中的 p53 活性没有影响。与 Tax 对 p53 的负面影响一致，转染 HTLV-1 感染的 T 细胞系后，未观察到 p53 响应启动子有活性。 p53蛋白在细胞核中高水平表达，HTLV-1感染的T细胞的核提取物与含有p53反应元件的DNA寡核苷酸组成型结合，表明Tax不会干扰p53与DNA的结合，Tax能够在三种不同的细胞系中抑制p53的反式激活功能，并且这种抑制需要Tax介导的CREB/ATF激活，而不是NF-kappa B/c-Rel通路， Tax 和活性 Tax 突变体能够消除 p53 诱导的 G(1) 停滞和细胞凋亡，并且这种效应与核 p53 定位的改变或 p53-DNA 复合物的破坏无关。 Tax 对 p53 活性的抑制对于 HTLV-1 诱导的 T 细胞永生化可能很重要。
Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) transforms human T cells in vitro, and Tax, a patent transactivator of viral and cellular genes, plays a key role in cell immortalization, Tax activity is mediated by interaction with cellular transcription factors including members of the CREB/ATF family, the NF-kappa B/c-Rel family, serum response factor, and the coactivators CREB binding protein-p300. Although p53 is usually not mutated in HTLV-1-infected T cells, its half-life is increased and its function is impaired, Here we report that transient coexpression of p53 and Tax results in the suppression of p53 transcriptional activity. Expression of Tax abrogates p53-induced G(1) arrest in the Calu-6 cell line and prevents the apoptosis induced by overexpressing p53 in the HeLa/Tat cell line. The Tax mutants M22 and G148V, which selectively activate the CREB/ATF pathway, exert these same biological effects on p53 function. In contrast, the NF-kappa B-active Tax mutant M47 has no effect on p53 activity in any of these systems. Consistent with the negative effect of Tax on p53, no activity on a p53-responsive promoter was observed upon transfection of HTLV-1-infected T-cell lines. The p53 protein is expressed at high levels in the nucleus, and nuclear extracts of HTLV-1-infected T cells bind constitutively to a DNA oligonucleotide containing the p53 response element, indicating that Tax does not interfere with p53 binding to DNA, Tax is able to suppress the transactivation function of p53 in three different cell lines, and this suppression required Tax-mediated activation of the CREB/ATF, but not the NF-kappa B/c-Rel, pathway, Tax and the active Tax mutants were able to abrogate the G(1) arrest and apoptosis induced by p53, and this effect does not correlate with an altered localization of nuclear p53 or with the disruption of p53-DNA complexes. The suppression of p53 activity by Tax could be important in T-cell immortalization induced by HTLV-1.