The roles of Tax encoded by HTLV on cell proliferation

人类T细胞白血病病毒（HTLV）是导致成人T细胞白血病（ATL）发生的病原体。由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。本研究旨在阐明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。我们使用Rat 1细胞分析了p21 waf在Tax表达细胞中的作用，其中内源性p21 waf表达由于其启动子的甲基化而受损。通过比较异位表达Tax和Tax + p21waf的细胞，我们观察到Tax + p21waf表达的细胞具有抗凋亡的特性。(2)By分析获得抗凋亡功能的分子机制 关于我们 在表达Tax和p21waf细胞中，我们发现这些细胞激活NF κ B信号。特别是，值得注意的是，NFkB信号传导的激活是通过非常规途径。因此，我们认为p21waf有助于与Tax一起激活这种信号传导。（3）HTLV的表达常因其LTR的甲基化而沉默。宿主细胞可能已经通过这种方式开发了关闭HTLV增殖的机制。然而，通过刺激感染细胞的增殖，经常发生HTLV基因表达的再激活。我们分析了Tax是否激活甲基化LTR的转录。该分析是在与Tax对各种甲基化启动子的反式作用活性的比较下进行的。我们发现，含有CRE序列的启动子可以被Tax激活，而不管CREB的存在，这表明不仅甲基化的LTR，而且含有CRE的其他细胞启动子也可以是Tax的靶点，即使是高度甲基化的。因此，本研究为理解Tax在转录调控方面更为复杂的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