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2015 ; 50
(5
): 393-426
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Mediator kinase module and human tumorigenesis
#MMPMID26182352
Clark AD
; Oldenbroek M
; Boyer TG
Crit Rev Biochem Mol Biol
2015[]; 50
(5
): 393-426
PMID26182352
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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.
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