Mediator kinase module and human tumorigenesis

Alison D. Clark, Marieke Oldenbroek, Thomas G Boyer

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)393-426
Number of pages34
JournalCritical Reviews in Biochemistry and Molecular Biology
Volume50
Issue number5
DOIs
StatePublished - Sep 3 2015

Keywords

  • Cancer
  • development
  • Mediator
  • RNA polymerase II transcription
  • signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry

Fingerprint Dive into the research topics of 'Mediator kinase module and human tumorigenesis'. Together they form a unique fingerprint.

  • Cite this