p53 Functional Impairment and High <sub>p</sub>21<sup>waf1/cip1</sup> Expression in Human T-Cell Lymphotropic/Leukemia Virus Type I -Transformed T Cells

Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53-regulated gene, p21waf1/cip1(wild-type p53 activated fragment 1/ cycling dependent kinases [cdks] interacting protein 1), in HTLV-l–infected T cells. We have found that the majority of HTLV-I–infected T cells have the wild-type p53 gene. However, its function in HTLV-l–transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene,p21waf1/cip1, is elevated at the messenger ribonucleic acid and protein levels in all HTLV-l–infected T-cell lines examined as well as in Taxl-1, a human T-cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21waf1/cip1promoter-driven luciferase gene in p53 null cells, and increases p21waf1/cip1expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21waf1/cip1in HTLV-l–infected cells. Dysregulation of p53 and p21waf1/cip1proteins regulating cell-cycle progression, may represent an important step in HTLV-l–induced T-cell transformation.

人类T细胞嗜淋巴细胞/白血病病毒I型（HTLV - I）在体内和体外均与T细胞转化有关。尽管一些导致转化的机制仍不清楚，但越来越多的证据支持病毒以及失调的细胞蛋白在转化中起直接作用。我们研究了肿瘤抑制基因p53以及受p53调控的基因p21waf1/cip1（野生型p53激活片段1/细胞周期蛋白依赖性激酶[cdks]相互作用蛋白1）在HTLV - I感染的T细胞中的潜在作用。我们发现大多数HTLV - I感染的T细胞具有野生型p53基因。然而，它在HTLV - I转化细胞中的功能似乎受损，这表现为对电离辐射（IR）缺乏适当的由p53介导的反应。有趣的是，在所有检测的HTLV - I感染的T细胞系以及稳定表达Tax的人类T细胞系Taxl - 1中，p53诱导基因p21waf1/cip1在信使核糖核酸和蛋白质水平上的表达均升高。此外，Tax在p53缺失细胞中诱导p21waf1/cip1启动子驱动的荧光素酶基因上调，并增加Jurkat T细胞中p21waf1/cip1的表达。这些发现表明，Tax蛋白至少在部分程度上导致了HTLV - I感染细胞中p21waf1/cip1的不依赖p53的表达。调节细胞周期进程的p53和p21waf1/cip1蛋白的失调可能是HTLV - I诱导T细胞转化的一个重要步骤。