Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit "kinase" module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways.

中文翻译：

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介体激酶模块和人类肿瘤发生。

介体是一种保守的多亚基信号处理器，通过该处理器，由基因特异性转录因子传达的调控信息被转导至RNA聚合酶II（Pol II）。在人类中，MED13，MED12，CDK8和细胞周期蛋白C（CycC）包含一个四亚基“激酶”模块，该模块与26个亚基介体核心可变连接。遗传和生化研究已将介体激酶模块确定为通过介体发展和致癌信号转导的主要途径，其在信号依赖性基因调控中的许多功能都源自其固有的CDK8激酶活性。例如，靶向CDK8的底物磷酸化会影响转录因子半衰期，Pol II活性以及染色质化学和功能状态。最近的结构和生化研究已经揭示了正确的激酶模块活性所需的物理和功能性亚基相互作用的精确网络。因此，通过改变组成性激酶模块亚基的表达或突变，该活性的病理学改变可对改变的信号传导和肿瘤形成产生深远的影响。在这里，我们审查介导激酶模块的结构组织，生物学功能和致癌的潜力。我们主要集中于激酶模块亚基中的肿瘤相关改变，为此建立了与严格相关关联相反的机制关系。这些考虑因素表明，介导的激酶模块是一种致癌单元，一种通过成分改变引起的致病性激活/失活通过干扰信号依赖性基因调节来驱动肿瘤形成的方法。因此，对抗CDK8驱动的肿瘤的治疗策略将涉及CDK8活性的靶向调节或CDK8依赖性信号传导途径失调的药理处理。