Protein phosphatase 2A activates the HIV-2 promoter through enhancer elements that include the pets site
Protein phosphatase 2A activates the HIV-2 promoter through enhancer elements that include the pets site
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DOI：
10.1074/jbc.m006454200
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发表时间：
2001-07-13
影响因子：
4.8
通讯作者：
Markovitz, DM
中科院分区：
文献类型：
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作者：
Faulkner, NE;Hilfinger, JM;Markovitz, DM
人类免疫缺陷病毒2型(HIV-2)基因的表达受上游启动子元件的调控，包括pETS(peri-ets，pETS)位点，它介导了佛波酯12-O-十四酰佛波醇-13-乙酸酯(TPA)处理后的增强子刺激。我们以前证明，癌蛋白dek以一种位点特异性的方式与pETS位点结合。在这份报告中，我们证明了与HIV-2 pETS结合是通过TPA处理U937单核细胞来调节的，TPA是蛋白激酶C的激活剂，TPA处理导致DEK水平降低，并在凝胶位移分析中形成更快迁移的PETS复合体。我们进一步证明，TPA对PETS结合的作用可以被核蛋白的磷酸酶处理所复制，并被蛋白磷酸-2A(PP2A)抑制剂冈田酸所阻断。最后，我们证明了PP2A催化结构域的异位表达可以单独激活HIV-2增强子/启动子，也可以与TPA协同激活，这一效应部分是通过PETS位点介导的。这些结果表明，通过与蛋白激酶C途径的相互作用，PP2A强烈参与调节HIV-2增强子介导的转录。这是由于它影响DEK的表达和与PETS位点的结合，以及它对其他启动子元件的影响。这些发现不仅对HIV-2转录有影响，而且对涉及DEK或PP2A的多种细胞过程也有影响。
Human immunodeficiency virus type 2 (HIV-2) gene expression is regulated by upstream promoter elements, including the peri-Ets (pets) site, which mediate enhancer stimulation following treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), We previously showed that the oncoprotein DEK binds to the pets site in a site-specific manner. In this report, we show that binding to the HIV-2 pets site is modulated by treatment of U937 monocytic cells with TPA, an activator of protein kinase C, TPA treatment resulted in a reduction in the levels of DEK and the formation of a faster migrating pets complex in gel shift assays. We show further that the actions of TPA on pets binding can be duplicated by phosphatase treatment of nuclear proteins and is blocked with okadaic acid, a protein phospatase-2A (PP2A) inhibitor. Finally, we demonstrate that ectopic expression of the catalytic domain of PP2A can activate the HIV-2 enhancer/promoter alone or in synergy with TPA, an effect mediated in part through the pets site. These results suggest that, through an interaction with the protein kinase C pathway, PP2A is strongly involved in regulating HIV-2 enhancer-mediated transcription. This is a consequence of its effects on DEK expression and binding to the pets site, as well as its effects on other promoter elements. These findings have implications not only for HIV-2 transcription but also for multiple cellular processes involving DEK or PP2A.