The roles of Tax encoded by HTLV on cell proliferation

人T细胞白血病病毒(HTLV)是成人T细胞白血病(ATL)的致病因子。已知HTLV编码的Tax在肿瘤的发展过程中起着重要作用。然而，税收在这一过程中的确切作用机制仍有待阐明。在这里，我们着重阐明了Tax在细胞增殖调控、转录调控和表观遗传调控中的作用，发现了以下证据：(1)Tax表达后，参与细胞周期调控的细胞蛋白p21waf表达上调。我们利用Rat1细胞分析了p21waf在Tax表达细胞中的作用，在Rat1细胞中，内源性p21waf的表达因其启动子的甲基化而受到抑制。通过对表达异位Tax的细胞和表达Tax+p21waf的细胞的比较，我们观察到表达Tax+p21waf的细胞具有抗凋亡的特性。(2)通过分析…获得抗细胞凋亡功能的分子机制在那些表达Tax和p21waf的细胞中，我们发现这些细胞激活了NFkB信号。特别值得注意的是，NFkB信号的激活是通过非常规途径进行的。因此，我们认为p21waf与Tax一起参与了这一信号的激活。(3)HTLV的表达常常被其LTR的甲基化所抑制。宿主细胞可能通过这种方式发展了阻止HTLV增殖的机制。然而，通过刺激感染细胞的增殖，经常会发生HTLV基因表达的重新激活。我们分析了Tax是否激活了甲基化LTR的转录。该分析是在比较不同甲基化启动子的TAX的交易活性的情况下进行的。我们发现，含有Cre序列的启动子可以被Tax激活，而与CREB的存在无关，这表明不仅甲基化的LTR，而且其他带有Cre的细胞启动子也可以成为Tax的靶标，即使高度甲基化也是如此。因此，这项研究为理解更复杂的税收转录调控机制提供了新的线索。较少

Human T-cell leukemia virus, HTLV, is a causative agent for the development of adult T-cell leukemia, ATL. Tax encoded by HTLV has been known to play important roles in the process of development of the tumor. However, precise mechanism of Tax in this process still remains to be elucidated. Here, we focused to clarify the roles of Tax in regulations of cell proliferation, transcriptional regulation and epigenetic regulation, and found the following evidence ; (1)Upon Tax expression, a cellular protein, p21waf, which involves in cell cycle regulation, was up-regulated. We analyzed the role of p21waf in Tax expressing cells using Rat1 cell in which endogenous p21waf expression is impaired because of methylation of its promoter. By comparison of cells expressing ectopic Tax, and those expressing tax plus p21waf, we observed that the cells expressing Tax plus p21waf showed characteristics nature, resistant to apoptosis. (2)By analyzing molecular mechanism of gaining anti-apoptotic function … More in those cells expressing Tax and p21waf, we found that these cells activated NFkB signaling. In particular, it is note worthy that activation of NFkB signaling was through a non-conventional pathway. Thus, we believe that p21waf contributes to activate this signaling together with Tax. (3)Expression of HTLV is often silenced by methylation of its LTR. Host cells may have developed the mechanism to shut down proliferation of HTLV by this way. However, by stimulation of proliferation of the infected cells, re-activation of gene expression of HTLV often occurs. We analyzed whether or not Tax activate transcription from methylated LTR. This analysis was conducted under comparison with transacting activity of Tax for various methylated promoter. We found that the promoter containing CRE sequence could be activated by Tax irrespective to presence of CREB, which suggests not only the methylated LTR but also other cellular promoters with CRE can be the target for Tax even heavily methylated. Thus, this study provides a new clue to understand more complicated mechanism of Tax in regard to transcriptional regulation. Less