Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein brd4
Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein brd4
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DOI：
10.1016/j.molcel.2005.06.029
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发表时间：
2005-08-19
期刊：
影响因子：
16
通讯作者：
Zhou, Q
中科院分区：
文献类型：
--
作者：
Yang, ZY;Yik, JHN;Zhou, Q
构成核心正性转录延伸因子b（P - TEFb）的细胞周期蛋白T1（cyclinT1）/细胞周期蛋白依赖性激酶9（Cdk9）异二聚体通常被认为是刺激RNA聚合酶II延伸的转录活性形式。大约一半的细胞内P - TEFb也以无活性复合物的形式与7SK小核RNA和HEXIM1蛋白结合存在。在此，我们表明剩余的一半与含溴结构域蛋白Brd4结合。在应激诱导的细胞中，与7SK/HEXIM1结合的P - TEFb定量地转化为与Brd4相关的形式。与Brd4的结合对于形成有转录活性的P - TEFb是必需的，它将P - TEFb招募到启动子，并使P - TEFb能够与中介体复合物接触，中介体复合物是Brd4介导招募的一个潜在靶点。尽管对于转录通常是必需的，但Brd4招募P - TEFb的功能可被HIV - 1 Tat的相应功能所替代，HIV - 1 Tat直接招募P - TEFb以激活HIV - 1转录。Brd4、HEXIM1和7SK都与调节细胞生长有关，这可能是由于它们对通用转录因子P - TEFb的动态调控所致。
The cyclinT1/Cdk9 heterodimer that constitutes core P-TEFb is generally presumed to be the transcriptionally active form for stimulating RNA polymerase 11 elongation. About half of cellular P-TEFb also exists in an inactive complex with the 7SK snRNA and the HEXIM1 protein. Here, we show that the remaining half associates with the bromodomain protein Brd4. In stress-induced cells, the 7SK/HEXIM1-bound P-TEFb is quantitatively converted into the Brd4-associated form. The association with Brd4 is necessary to form the transcriptionally active P-TEFb, recruits P-TEFb to a promoter, and enables P-TEFb to contact the Mediator complex, a potential target for the Brd4-mediated recruitment. Although generally required for transcription, the P-TEFb-recruitment function of Brd4 can be substituted by that of HIV-1 Tat, which recruits P-TEFb directly for activated HIV-1 transcription. Brd4, HEXIM1, and 7SK are all implicated in regulating cell growth, which may result from their dynamic control of the general transcription factor P-TEFb.