Mediator kinase module and human tumorigenesis.
Mediator kinase module and human tumorigenesis.
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DOI：
10.3109/10409238.2015.1064854
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发表时间：
2015
影响因子：
6.5
通讯作者：
Boyer TG
中科院分区：
文献类型：
--
作者：
Clark AD;Oldenbroek M;Boyer TG
中介体是一个保守的多亚基信号处理器，通过它，基因特异性转录因子传递的调控信息被转导到RNA聚合酶II （Pol II）。在人类中，MED13、MED12、CDK8和Cyclin C （CycC）包含一个4亚基的“激酶”模块，该模块与26亚基的Mediator核心存在可变关联。遗传和生化研究已经确立了中介激酶模块是通过中介介导发育和致癌信号的主要入口，其在信号依赖性基因调控中的大部分功能源于其驻留的CDK8激酶活性。例如，cdk8靶向底物磷酸化影响转录因子半衰期、Pol II活性、染色质化学和功能状态。最近的结构和生化研究揭示了正确的激酶模块活性所需的物理和功能亚基相互作用的精确网络。因此，通过改变激酶模块亚基的表达或突变，这种活性的病理变化可能对信号传导和肿瘤形成的改变产生深远的影响。在此，我们综述了中介激酶模块的结构组织、生物学功能和致癌潜力。我们主要关注激酶模块亚基的肿瘤相关改变，其机制关系而不是严格相关的关联已经建立。这些考虑指向了中介激酶模块作为一个致癌单元的新图景，其中通过组分变化的致病性激活/失活通过信号依赖性基因调控的扰动驱动肿瘤形成。因此，对抗CDK8驱动肿瘤的治疗策略将涉及靶向调节CDK8活性或对失调的CDK8依赖性信号通路进行药理学操作。
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.