Peroxisome proliferator-activated receptor γ recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis
Peroxisome proliferator-activated receptor γ recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis
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DOI：
10.1210/me.2005-0222
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发表时间：
2006-07-01
影响因子：
--
通讯作者：
Fajas, Lluis
中科院分区：
文献类型：
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作者：
Iankova, Irena;Petersen, Rasmus K.;Fajas, Lluis
正转录延伸因子 b(P-TEFb) 磷酸化 RNA 聚合酶 II 的 C 末端结构域，促进转录延伸。除了参与一般转录外，P-TEFb 还被一些转录因子（例如 c-Myc 或 MyoD）招募到特定启动子。 P-TEFb 复合物由细胞周期蛋白依赖性激酶 (cdk9) 亚基和调节伙伴（细胞周期蛋白 T1、细胞周期蛋白 T2 或细胞周期蛋白 K）组成。由于 cdk9 已被证明参与分化过程，例如肌肉细胞分化，因此我们研究了 cdk9 在脂肪形成中的可能作用。在这项研究中，我们发现 cdk9 p55 亚型的表达在 3T3-L1 脂肪细胞分化过程中在 RNA 和蛋白质水平上受到高度调节。此外，cdk9 以及细胞周期蛋白 T1 和细胞周期蛋白 T2 在脂肪形成的不同阶段显示出核定位的差异。 cdk9 的过度表达增加了 3T3-L1 细胞的脂肪形成潜力，而特定 cdk 抑制剂和显性失活 cdk9 突变体对 cdk9 的抑制会损害脂肪形成。我们发现，cdk9 对 3T3-L1 细胞分化的积极作用是通过与过氧化物酶体增殖物激活受体 γ (PPAR γ) 的直接相互作用和磷酸化介导的，PPAR γ 是该过程的主要调节因子，在 PPAR γ 靶基因的启动子上。 PPAR gamma-cdk9 相互作用导致 PPAR gamma 转录活性增加，从而增加脂肪生成。
Positive transcription elongation factor b(P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c-Myc or MyoD. The P-TEFb complex is composed of a cyclin-dependent kinase (cdk9) subunit and a regulatory partner ( cyclin T1, cyclin T2, or cyclin K). Because cdk9 has been shown to participate in differentiation processes, such as muscle cell differentiation, we studied a possible role of cdk9 in adipogenesis. In this study we show that the expression of the cdk9 p55 isoform is highly regulated during 3T3-L1 adipocyte differentiation at RNA and protein levels. Furthermore, cdk9, as well as cyclin T1 and cyclin T2, shows differences in nuclear localization at distinct stages of adipogenesis. Overexpression of cdk9 increases the adipogenic potential of 3T3-L1 cells, whereas inhibition of cdk9 by specific cdk inhibitors, and dominant-negative cdk9 mutant impairs adipogenesis. We show that the positive effects of cdk9 on the differentiation of 3T3-L1 cells are mediated by a direct interaction with and phosphorylation of peroxisome proliferator-activated receptor gamma(PPAR gamma), which is the master regulator of this process, on the promoter of PPAR gamma target genes. PPAR gamma-cdk9 interaction results in increased transcriptional activity of PPAR gamma and therefore increased adipogenesis.