Dominant negative mutant cyclin T1 proteins inhibit HIV transcription by specifically degrading Tat.
Dominant negative mutant cyclin T1 proteins inhibit HIV transcription by specifically degrading Tat.
复制标题
DOI：
10.1186/1742-4690-5-63
复制
发表时间：
2008-07-11
期刊：
影响因子：
3.3
通讯作者：
Fujinaga K
中科院分区：
文献类型：
--
作者：
Jadlowsky JK;Nojima M;Schulte A;Geyer M;Okamoto T;Fujinaga K
正性转录延伸因子b(P-TEFb)是人类免疫缺陷病毒1型(HIV-1)转录所必需的细胞辅因子。P-TEFb的Cyclin T1(CycT1)亚单位与病毒蛋白Tat结合在反式激活反应元件(TAR)上。这是刺激转录延长的关键和必要的一步。因此，CycT1可能成为抗HIV药物开发的潜在靶点。为了创造有效的HIV转录抑制物，根据CycT1与其他周期蛋白分子的序列相似性以及CycT1的晶体结构，构建了突变的CycT1蛋白。其中一个突变体，命名为CycT1-U7，尽管稳定表达水平非常低，但对依赖TAT的HIV转录显示出强大的显性负面效应。令人惊讶的是，与CycT1-U7共表达的TAT蛋白的表达水平显著低于与野生型CycT1共表达的TAT蛋白。但经蛋白酶体抑制剂处理后，CycT1-U7和TAT的表达水平有所恢复。同时，这些抑制剂消除了CycT1-U7的显性负性作用。这些结果表明，CycT1-U7通过促进TAT的快速降解来抑制HIV的转录。这些突变的CycT1蛋白代表了一类新型的HIV转录特异性抑制物，可能用于抗病毒治疗的设计。
The positive transcription elongation factor b (P-TEFb) is an essential cellular co-factor for the transcription of the human immunodeficiency virus type 1 (HIV-1). The cyclin T1 (CycT1) subunit of P-TEFb associates with a viral protein, Tat, at the transactivation response element (TAR). This represents a critical and necessary step for the stimulation of transcriptional elongation. Therefore, CycT1 may serve as a potential target for the development of anti-HIV therapies. To create effective inhibitors of HIV transcription, mutant CycT1 proteins were constructed based upon sequence similarities between CycT1 and other cyclin molecules, as well as the defined crystal structure of CycT1. One of these mutants, termed CycT1-U7, showed a potent dominant negative effect on Tat-dependent HIV transcription despite a remarkably low steady-state expression level. Surprisingly, the expression levels of Tat proteins co-expressed with CycT1-U7 were significantly lower than Tat co-expressed with wild type CycT1. However, the expression levels of CycT1-U7 and Tat were restored by treatment with proteasome inhibitors. Concomitantly, the dominant negative effect of CycT1-U7 was abolished by these inhibitors. These results suggest that CycT1-U7 inhibits HIV transcription by promoting a rapid degradation of Tat. These mutant CycT1 proteins represent a novel class of specific inhibitors for HIV transcription that could potentially be used in the design of anti-viral therapy.
登录
查看更多内容
影响因子：
5.6
作者：
Anand, Kanchan;Schulte, Antie;Geyer, Matthias
通讯作者：
Geyer, Matthias
影响因子：
4.8
作者：
Bai, JR;Sui, JH;Marasco, WA
通讯作者：
Marasco, WA
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
影响因子：
5.3
作者：
Hoque, M;Young, TM;Pe'ery, T
通讯作者：
Pe'ery, T
影响因子：
5.4
作者：
Fujinaga, K;Irwin, D;Peterlin, BM
通讯作者：
Peterlin, BM