P-TEFb is a crucial co-factor for Myc transactivation
P-TEFb is a crucial co-factor for Myc transactivation
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DOI：
10.4161/cc.6.16.4554
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发表时间：
2007-08-15
期刊：
影响因子：
4.3
通讯作者：
Lania, Luigi
中科院分区：
文献类型：
--
作者：
Gargano, Barbara;Amente, Stefano;Lania, Luigi
MYC形成具有最大的异二聚体，并在与细胞染色质中特定DNA位点结合后作为转录因子起作用。除了募集组蛋白乙酰化活性外，MYC还与阳性转录伸长因子B（P-TEFB）结合，该因子B（P-TEFB）由细胞周期蛋白依赖性激酶CKD9及其调节性亚基Cyclin T. P-Tefb磷酸化，可磷酸RNA聚合酶II的较大亚基以及负伸长因子，允许有效转录伸长。在这里，我们报告说，MYC与Max的异二聚体结合，仅是核心活动P-TEFB复合物，并且它在体内募集了MYC目标的P-TEFB。 5.6-二氯-1-B-D-核呋喃糖基 - 辛咪唑（DRB）对P-TEFB的药理抑制（DRB）特异性抑制了Myc响应的CAD和NUC基因的表达，并损害MyC诱导的S型S相和生长的S-相生长的细胞倍增。在低血清中。染色质免疫沉淀测定法（CHLP）表明，MYC和P-TEFB与CAD和NUC e-boxes的同时占领，DRB处理降低了在其CTD的Ser-2上磷酸化的POL II磷酸化的密度。这些结果表明，P-TEFB在体内募集到Myc-Target启动子，CDK9活性是依赖MYC依赖响应基因的重要步骤。
Myc forms an heterodimer with Max and operates as a transcription factor upon binding to specific DNA sites in cellular chromatin. In addition to recruit histone acetylation activity, Myc binds to the positive transcription elongation factor b (P-TEFb) which consists of the cyclin-dependent kinase CKD9 and its regulatory subunit cyclin T. P-TEFb phosphorylates the carboxyl-terminal-domain (CTD) of the larger subunit of RNA polymerase II as well as negative elongation factors allowing efficient transcription elongation. Here, we report that Myc binds, as heterodimer with Max, exclusively the core active P-TEFb complex, and it recruits P-TEFb at Myc targets in vivo. Pharmacological inhibition of P-TEFb by 5.6-di-chloro-1-b-D-ribofuranosyl-bensimidazole (DRB) specifically inhibits expression of Myc-responsive CAD and NUC genes, and impairs the Myc-induced S-phase and apoptosis of quiescent cells grown in low serum. Chromatin immunoprecipitation assays (ChlP)demonstrated co-occupancy of Myc and P-TEFb to CAD and NUC E-boxes, and DRB treatment diminished the density of Pol II phosphorylated on Ser-2 of its CTD. These results indicate that P-TEFb is recruited in vivo to Myc-target promoters and CDK9 activity is an important step for Myc-dependent stimulation of responsive genes.