Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Biochem Biophys Res Commun. 2018 Jun 7;500(3):538-543. doi: 10.1016/j.bbrc.2018.04.062. Epub 2018 Apr 23.
HTLV-1 and HIV-1 are retroviruses involved in different human diseases. However, following infection, these viruses inter into a latent state. Tax and Tat are regarded as trans-activators of HTLV-1 and HIV-1 respectively. As it known, during the latent state the infected cells contain low Tax and Tat protein levels, so the activation of these viruses must be independent of these proteins. Here we focus on exploring the mechanism of activation of these viruses by 12-O-tetradecanoylphorbol-13-acetate (TPA), which is a potent activator of protein kinase C (PKC) and considered as a stress-inducing agent. Our results showed that short exposure to TPA considerably stimulated only the HIV-1 LTR expression, while long exposure stimulated only the HTLV-1 LTR and that their activation is agonized or antagonized by PKC respectively. It was found that TPA induced interaction between the transcriptional factors Sp1 and P53 producing Sp1-p53 complex which strongly interacted with c-Jun only after short exposure to TPA. In addition, TPA treatment highly induced the expression of CREB which attached to the Sp1-p53 complex mainly after a long exposure to TPA. A strong binding of sp1, p53 and CREB proteins with HTLV-1 LTR and strong binding of NF-κB with HIV-1 LTR were observed after long (24 h) and short (6 h) exposures to TPA respectively by Chip assay. These results support the possibility that sp1, p53 and CREB are involved in the TPA induced HTLV-1 LTR expression while TPA activation of HIV-1 LTR seems to be dependent on PKC activity through the NF-κB pathway.
HTLV-1 和 HIV-1 是两种与不同人类疾病相关的逆转录病毒。然而，在感染后，这些病毒进入潜伏状态。Tax 和 Tat 分别被认为是 HTLV-1 和 HIV-1 的反式激活因子。众所周知，在潜伏状态下，受感染的细胞中含有低水平的 Tax 和 Tat 蛋白，因此这些病毒的激活必须独立于这些蛋白。在这里，我们专注于研究 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）激活这些病毒的机制，TPA 是蛋白激酶 C（PKC）的有效激活剂，被认为是一种应激诱导剂。我们的结果表明，短时间暴露于 TPA 可显著刺激仅 HIV-1 LTR 的表达，而长时间暴露仅刺激 HTLV-1 LTR 的表达，其激活分别被 PKC 促进或拮抗。发现 TPA 诱导转录因子 Sp1 和 P53 之间的相互作用，产生 Sp1-p53 复合物，只有在短时间暴露于 TPA 后才与 c-Jun 强烈相互作用。此外，TPA 处理高度诱导 CREB 的表达，其主要在长时间暴露于 TPA 后附着于 Sp1-p53 复合物上。通过 Chip 检测，发现短时间（6 小时）和长时间（24 小时）暴露于 TPA 后，HTLV-1 LTR 上观察到 sp1、p53 和 CREB 蛋白与 NF-κB 与 HIV-1 LTR 的强结合，HTLV-1 LTR 上观察到 sp1、p53 和 CREB 蛋白与 HTLV-1 LTR 的强结合。这些结果支持这样一种可能性，即 sp1、p53 和 CREB 参与 TPA 诱导的 HTLV-1 LTR 表达，而 TPA 激活 HIV-1 LTR 似乎依赖于 PKC 活性通过 NF-κB 途径。
