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重要作用。然而，税收在这一过程中的确切机制仍有待阐明。本文重点阐明了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)表达Tax后，参与细胞周期调控的细胞蛋白p21waf上调。我们利用Rat1细胞分析了p21waf在表达Tax的细胞中的作用，在Rat1细胞中，内源性p21waf的表达因其启动子甲基化而受损。通过比较表达异位Tax和表达Tax + p21waf的细胞，我们发现表达Tax + p21waf的细胞表现出抗凋亡的特性。(2)通过分析表达Tax和p21waf的细胞获得抗凋亡功能的分子机制，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和Tax共同激活了这一信号。(3) HTLV的表达常因其LTR甲基化而沉默，宿主细胞可能通过这种方式发展出了抑制HTLV增殖的机制。然而，通过刺激感染细胞的增殖，HTLV基因表达的再激活经常发生。我们分析了Tax是否激活了LTR甲基化的转录，并与不同甲基化启动子对Tax的交易活性进行了比较。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，而且含有CRE的其他细胞启动子即使重度甲基化也可以成为Tax的目标。因此，本研究为理解更复杂的税收转录调控机制提供了新的线索。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