Cooperativity between Rad51 and C/EBP family transcription factors modulates basal and tat-induced activation of the HIV-1 LTR in astrocytes
Cooperativity between Rad51 and C/EBP family transcription factors modulates basal and tat-induced activation of the HIV-1 LTR in astrocytes
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DOI：
10.1002/jcp.20612
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发表时间：
2006-06-01
影响因子：
5.6
通讯作者：
Amini, S
中科院分区：
文献类型：
--
作者：
Chipitsyna, G;Sawaya, BE;Amini, S
HIV-1基因组的转录是一个复杂的事件，需要识别LTR序列的细胞蛋白与病毒蛋白（最值得注意的是达特）的功能和物理通信。此外，研究还揭示了达特诱导多种细胞基因转录的能力，这些基因的产物可以影响细胞的状态，从而有助于艾滋病的发病机制。最近，我们证明了星形胶质细胞和其他神经细胞中达特的表达会导致拉德51的上调，拉德51是通过同源重组进行DNA修复的主要成分。Rad 51的非计划性上调反过来又对Tat产生细胞中观察到的染色体异常程度产生影响。在这里，我们询问Rad 51水平的升高是否影响星形胶质细胞中病毒基因转录的程度。我们的研究结果表明，异位表达Rad 51增强了基础和Tat诱导的LTR启动子的转录。该事件需要来自转录因子的C/EBP家族的协同性，包括C/EBP β和C/EBP β同源蛋白（CHOP）。与达特类似，我们发现Rad 51与C/EBP β相互作用，并增强其与跨越LTR的核苷酸-120至-94的DNA基序的相互作用。有趣的是，达特表现出增强Rad 51和C/EBP β之间协同作用的能力。我们的研究结果还表明，CHOP和达特单独或一起激活LTR的水平在SW 1/SNF 1染色质重塑复合物存在下升高。这些观察结果揭示了LTR的达特激活的新途径，其包括涉及Rad 51和C/EBP β家族蛋白的正反馈环。
Transcription of the HIV-1 genome is a complex event that requires functional and physical communication of cellular proteins that recognize the LTR sequence with viral proteins, most notably, Tat. Moreover, studies have revealed the ability of Tat to induce transcription of a variety of cellular genes whose products can affect the status of cells, thus contributing to the pathogenesis of AIDS. Recently, we demonstrated that expression of Tat in astrocytes and other neural cells leads to upregulation of Rad51, a major component of DNA repair via homologous recombination. The unscheduled upregulation of Rad51, in turn, has an impact upon the extent of chromosomal abnormalities that are seen in Tat-producing cells. Here, we asked whether an elevation in Rad51 levels influences the extent of viral gene transcription in astrocytic cells. Our results demonstrate that ectopic expression of Rad51 enhances the basal- and the Tat-induced transcription of the LTR promoter. This event requires cooperativity from the C/EBP family of transcription factors including C/EBP beta and C/EBP beta homologous protein (CHOP). Similar to Tat, we showed that Rad51 interacts with C/EBP beta and augments its interaction with the DNA motif spanning nucleotides -120 to -94 of the LTR. Interestingly, Tat exhibited the capacity to augment the synergism between Rad51 and C/EBP beta. Our results also demonstrate that the level of activation of the LTR by CHOP and Tat, either alone or together, is elevated in the presence of the SW1/SNF1 chromatin remodeling complex. These observations unravel anew pathway for Tat activation of the LTR that includes the positive feedback loop involving Rad51 and C/EBP beta family proteins.