Brauweiler A, Garl P, Franklin A A, Giebler H A, Nyborg J K
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins 80523, USA.
J Biol Chem. 1995 May 26;270(21):12814-22. doi: 10.1074/jbc.270.21.12814.
The human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive T-cell malignancy in humans. While the virus appears to maintain a state of latency in most infected cells, high level virion production is an essential step in the HTLV-I life cycle. The virally-encoded Tax protein, a potent activator of gene expression, is believed to control the switch from latency to replication. Tax stimulation of HTLV-I transcription is mediated through cellular activating transcription factor/cAMP response element binding proteins, which bind the three 21-base pair (bp) repeat viral enhancer elements. In this report, we show that viral latency may result from a highly unstable interaction between CREB and the HTLV-I 21-bp repeats, resulting in rapid dissociation of CREB from the viral promoter. In the presence Tax, the dissociation rate of CREB from a 21-bp repeat element is decreased. This stabilization is highly specific, requiring the amino-terminal region of CREB and appropriate 21-bp repeat sequences. We suggest that Tax stabilization of CREB binding to the viral promoter leads to an increase in gene expression, possibly providing the switch from latency to high level replication of the virus.
人类I型T细胞白血病病毒（HTLV-I）是人类侵袭性T细胞恶性肿瘤的病原体。虽然该病毒在大多数受感染细胞中似乎维持潜伏状态，但高水平的病毒体产生是HTLV-I生命周期中的一个关键步骤。病毒编码的Tax蛋白是一种强大的基因表达激活剂，被认为控制着从潜伏到复制的转变。Tax对HTLV-I转录的刺激是通过细胞激活转录因子/ cAMP反应元件结合蛋白介导的，这些蛋白结合三个21碱基对（bp）重复的病毒增强子元件。在本报告中，我们表明病毒潜伏可能源于CREB与HTLV-I 21-bp重复序列之间高度不稳定的相互作用，导致CREB从病毒启动子快速解离。在存在Tax的情况下，CREB从21-bp重复元件的解离速率降低。这种稳定作用具有高度特异性，需要CREB的氨基末端区域和适当的21-bp重复序列。我们认为Tax使CREB与病毒启动子的结合稳定，导致基因表达增加，这可能为病毒从潜伏状态转变为高水平复制提供了条件。
