Abstract
CDK8 and its paralog, CDK19, collectively termed ‘Mediator Kinase,’ are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming. CDK8 and CDK19 are incorporated, in a mutually exclusive manner, as part of a 4-protein complex called the Mediator kinase module. This module reversibly associates with the Mediator, a 26 subunit protein complex that regulates RNA Polymerase II mediated gene expression. As part of this complex, the Mediator kinases have been implicated in diverse process such as developmental signaling, metabolic homeostasis and in innate immunity. In recent years, dysregulation of Mediator kinase module proteins, including CDK8/19, has been implicated in the development of different human diseases, and in particular cancer. This has led to intense efforts to understand how CDK8/19 regulate diverse biological outputs and develop Mediator kinase inhibitors that can be exploited therapeutically. Herein, we review both context and function of the Mediator kinases at a molecular, cellular and animal level. In so doing, we illuminate emerging concepts underpinning Mediator kinase biology and highlight certain aspects that remain unsolved.
Highlights
Transcription, the first stage of gene expression, is a fundamental cellular process by which genetic information (DNA) is converted to a molecule (RNA) that can exert a molecular phenotype
We describe the roles of the two Mediator kinases CDK8 and CDK19 in both normal tissue homeostasis and disease states
Mediator complex subunit 12 (MED12) and Mediator complex subunit 13 (MED13) are required for early eye development by regulating dac and dpp expression independently of CDK8 and CCNC, whereas all kinase module subunits function together in external sensory development (Loncle et al, 2007). These results demonstrate an essential function for the CDK8-kinase module during development, and suggest a kinase-independent function of MED12/MED13 in regulating gene expression
Summary
CDK8 and CDK19 are incorporated, in a mutually exclusive manner, as part of a 4-protein complex called the Mediator kinase module This module reversibly associates with the Mediator, a 26 subunit protein complex that regulates RNA Polymerase II mediated gene expression. As part of this complex, the Mediator kinases have been implicated in diverse process such as developmental signaling, metabolic homeostasis and in innate immunity. Dysregulation of Mediator kinase module proteins, including CDK8/19, has been implicated in the development of different human diseases, and in particular cancer This has led to intense efforts to understand how CDK8/19 regulate diverse biological outputs and develop Mediator kinase inhibitors that can be exploited therapeutically.
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