CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins.
CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins.
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DOI：
10.1093/nar/gkad538
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发表时间：
2023-08-11
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
--
作者：
我们对 CDK8 及其旁系同源物 CDK19 进行了详细的转录组学、蛋白质组学和磷酸化蛋白质组学分析，CDK19 是与转录介体复合物相关且与发育和疾病有关的激酶模块的替代酶组分。该分析是使用 CDK8 和 CDK19 的基因修饰、选择性 CDK8/19 小分子激酶抑制剂和有效的 CDK8/19 PROTAC 降解剂进行的。暴露于血清或 NFκB 或蛋白激酶 C (PKC) 激动剂的细胞中的 CDK8/19 抑制减少了信号响应基因的诱导，表明介导激酶在信号诱导的转录重编程中具有多效性作用。基础条件下的 CDK8/19 抑制最初下调了一小部分基因，其中大多数基因可通过血清或 PKC 刺激诱导。长期的 CDK8/19 抑制或诱变上调了更大的基因集，同时构成核心介体复合物及其激酶模块的蛋白质的转录后增加。 RNA 和蛋白质表达的调节都需要 CDK8/19 激酶活性，但这两种酶都以不依赖于激酶的方式保护其结合伴侣细胞周期蛋白 C 免受蛋白水解降解。对表达 CDK8、CDK19 或其激酶失活突变体的同基因细胞群的分析表明，CDK8 和 CDK19 在 RNA 和蛋白质水平上对蛋白质磷酸化和基因表达具有相同的定性影响，而 CDK8 与 CDK19 敲除的不同影响可归因于其表达和活性的定量差异，而不是功能不同。
We have conducted a detailed transcriptomic, proteomic and phosphoproteomic analysis of CDK8 and its paralog CDK19, alternative enzymatic components of the kinase module associated with transcriptional Mediator complex and implicated in development and diseases. This analysis was performed using genetic modifications of CDK8 and CDK19, selective CDK8/19 small molecule kinase inhibitors and a potent CDK8/19 PROTAC degrader. CDK8/19 inhibition in cells exposed to serum or to agonists of NFκB or protein kinase C (PKC) reduced the induction of signal-responsive genes, indicating a pleiotropic role of Mediator kinases in signal-induced transcriptional reprogramming. CDK8/19 inhibition under basal conditions initially downregulated a small group of genes, most of which were inducible by serum or PKC stimulation. Prolonged CDK8/19 inhibition or mutagenesis upregulated a larger gene set, along with a post-transcriptional increase in the proteins comprising the core Mediator complex and its kinase module. Regulation of both RNA and protein expression required CDK8/19 kinase activities but both enzymes protected their binding partner cyclin C from proteolytic degradation in a kinase-independent manner. Analysis of isogenic cell populations expressing CDK8, CDK19 or their kinase-inactive mutants revealed that CDK8 and CDK19 have the same qualitative effects on protein phosphorylation and gene expression at the RNA and protein levels, whereas differential effects of CDK8 versus CDK19 knockouts were attributable to quantitative differences in their expression and activity rather than different functions.
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影响因子：
8.8
作者：
Galbraith MD;Andrysik Z;Pandey A;Hoh M;Bonner EA;Hill AA;Sullivan KD;Espinosa JM
通讯作者：
Espinosa JM
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J
影响因子：
8
作者：
Barette, C;Jariel-Encontre, I;Piette, J
通讯作者：
Piette, J
影响因子：
5.6
作者：
Amirhosseini, Mehdi;Bernhardsson, Magnus;Fahlgren, Anna
通讯作者：
Fahlgren, Anna