Inhibition of Tat activity by the HEXIM1 protein.
Inhibition of Tat activity by the HEXIM1 protein.
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DOI：
10.1186/1742-4690-2-42
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发表时间：
2005-07-02
期刊：
影响因子：
3.3
通讯作者：
Lania L
中科院分区：
文献类型：
--
作者：
Fraldi A;Varrone F;Napolitano G;Michels AA;Majello B;Bensaude O;Lania L
正性转录延伸因子B（positive transcription elongation factor，P-TEF B）由CDK 9/CyclinT 1亚基组成，是HIV转录反式激活因子达特蛋白的一个专用辅因子。由HIV的长末端重复序列（LTR）驱动的转录涉及P-TEFb、达特和TAR元件之间的四级复合物的形成。这种募集对于增强来自HIV-1 5' LTR启动子的RNA Pol II的持续合成能力是必需的。P-TEFb的活性在体内和体外由HEXIM 1/7SK snRNA核糖核酸-蛋白质复合物调节。在这里，我们报告说，达特反式激活被有效地抑制HEXIM 1或其parasylum HEXIM 2的共表达。HEXIM 1表达特异性抑制通过人工募集GAL 4-CycT 1直接激活P-TEFb介导的转录。使用适当的HEXIM 1突变体，我们确定有效的Tat抑制需要7SK snRNA基本识别基序以及与细胞周期蛋白T1相互作用所需的C-末端区域。HEXIM 1蛋白表达增强适度影响P-TEFb活性，表明HEXIM 1介导的达特活性抑制不是由于细胞转录的全面抑制。这些结果指出P-TEFb对于达特的最佳转录活性的关键作用，并表明调节P-TEFb活性的细胞蛋白可能对体内达特功能产生深远影响。
The positive transcription elongation factor b (P-TEFb) composed by CDK9/CyclinT1 subunits is a dedicated co-factor of HIV transcriptional transactivator Tat protein. Transcription driven by the long terminal repeat (LTR) of HIV involves formation of a quaternary complex between P-TEFb, Tat and the TAR element. This recruitment is necessary to enhance the processivity of RNA Pol II from the HIV-1 5' LTR promoter. The activity of P-TEFb is regulated in vivo and in vitro by the HEXIM1/7SK snRNA ribonucleic-protein complex. Here we report that Tat transactivation is effectively inhibited by co-expression of HEXIM1 or its paralog HEXIM2. HEXIM1 expression specifically represses transcription mediated by the direct activation of P-TEFb through artificial recruitment of GAL4-CycT1. Using appropriate HEXIM1 mutants we determined that effective Tat-inhibition entails the 7SK snRNA basic recognition motif as well as the C-terminus region required for interaction with cyclin T1. Enhanced expression of HEXIM1 protein modestly affects P-TEFb activity, suggesting that HEXIM1-mediated repression of Tat activity is not due to a global inhibition of cellular transcription. These results point to a pivotal role of P-TEFb for Tat's optimal transcription activity and suggest that cellular proteins that regulate P-TEFb activity might exert profound effects on Tat function in vivo.
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