Vlach J, Garcia A, Jacqué J M, Rodriguez M S, Michelson S, Virelizier J L
Unite d'Immunologie Virale, Institut Pasteur, Paris, France.
Virology. 1995 Apr 20;208(2):753-61. doi: 10.1006/viro.1995.1207.
In contrast to the purely enhancer-dependent effect of cytokines such as TNF on the activity of the HIV regulatory region (LTR), we observed that okadaic acid (OKA) activates HIV transcription through both the enhancer, responding to the factor NF-kappa B, and the promoter domain of the LTR. The inducibility of HIV LTR-driven luciferase expression constructs in lymphoblastoid cells stimulated by OKA depended on both functional Sp1 binding elements and the ability of the TATA box to bind the protein TBP. In both transformed and normal lymphocytes, OKA stimulation induced intense phosphorylation of the constitutively expressed Sp1 protein in the nucleus, a property of OKA not shared by TNF, phorbol ester, or PHA and interleukin 2. Responsiveness of LTR constructs deleted of kappa B elements to HIV Tat expression was increased upon OKA but not TNF stimulation. Our results suggest that SP1 phosphorylation induced by OKA, a selective inhibitor of the serine-threonine phosphatase PP2A, facilitates the formation of a transcription complex involving general transcription factors, HIV Tat, and Sp1 proteins. The formation of this complex would increase, independently of an in synergy with NF-kappa B, the low basal activity of the HIV LTR observed in normal T lymphocytes.
与诸如肿瘤坏死因子（TNF）等细胞因子对HIV调控区（LTR）活性的纯粹增强子依赖性效应相反，我们观察到冈田酸（OKA）通过对因子NF-κB作出反应的增强子以及LTR的启动子结构域来激活HIV转录。在OKA刺激的淋巴母细胞中，HIV LTR驱动的荧光素酶表达构建体的诱导性既取决于功能性Sp1结合元件，也取决于TATA框结合蛋白质TBP的能力。在转化淋巴细胞和正常淋巴细胞中，OKA刺激均诱导细胞核中组成型表达的Sp1蛋白发生强烈磷酸化，这是TNF、佛波酯或PHA以及白细胞介素2所不具备的OKA特性。κB元件缺失的LTR构建体对HIV Tat表达的反应性在OKA刺激而非TNF刺激后增强。我们的结果表明，由丝氨酸-苏氨酸磷酸酶PP2A的选择性抑制剂OKA诱导的SP1磷酸化促进了涉及通用转录因子、HIV Tat和Sp1蛋白的转录复合物的形成。该复合物的形成将独立于与NF-κB的协同作用，增加在正常T淋巴细胞中观察到的HIV LTR的低基础活性。
