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Non-Cell Cycle Functions of Cell Cycle Regulators

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Front. Cell Dev. Biol. | doi: 10.3389/fcell.2018.00171

Molecular and in vivo functions of Mediator kinases CDK8 and CDK19

 Marius V. Dannappel1, Dhanya Sooraj1,  Jia J. Loh1, 2 and Ron Firestein1*
  • 1Centre for Cancer Research, Hudson Institute of Medical Research, Australia
  • 2School of Biological Sciences, Faculty of Science, Monash University, Australia

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 signalling, 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.

Keywords: Mediator kinase, Cyclin-depedent kinase, Cdk8, CDK19, developmental signaling, mouse models, develpoment, tissue homeostasis

Received: 06 Sep 2018; Accepted: 06 Dec 2018.

Edited by:

Gordon Chan, Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Canada

Reviewed by:

Randy Strich, Rowan University School of Osteopathic Medicine, United States
Matthew Galbraith, University of Colorado Denver, United States  

Copyright: © 2018 Dannappel, Sooraj, Loh and Firestein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Ron Firestein, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, 3168, Victoria, Australia, ron.firestein@hudson.org.au