Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases

Abstract

Transcriptional dysregulation is central to many diseases including cancer. Mutation or deregulated expression of proteins involved in transcriptional machinery leads to aberrant gene expression that disturbs intricate cellular processes of division and differentiation. The subunits of the mediator complex are master regulators of stimuli‐derived transcription and are essential for transcription by RNA polymerase II. MED12 is a part of the CDK8 kinase module of the mediator complex and is essential for kinase assembly and function. Other than its function in activation of the kinase activity of CDK8 mediator, it also brings about transcription repression or activation, in response to several signalling pathways, a function that is independent of its role as a part of kinase assembly. Accumulating evidence suggests that MED12 controls complex transcription programs that are defining in cell fate determination, differentiation, and carcinogenesis. Mutations or differential expression of MED12 manifest in several human disorders and diseases. For instance, MED12 mutations are the gold standard for the diagnosis of several X‐linked intellectual disability syndromes. Further, certain MED12 mutations are categorised as driver mutations in carcinogenesis as well. This is a timely review that provides for the first time a wholesome view on the critical roles and pathways regulated by MED12, its interactions along with the implications of MED12 alterations/mutations in various cancers and nonneoplastic disorders. Based on the preclinical studies, MED12 indeed emerges as an attractive novel therapeutic target for various diseases and intellectual disorders.

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

“…The activation helix is essential for the ability of MED12 to activate CDK8 kinase activity, although it is not essential for binding to the CCNC-CDK8 complex. This model, in which precise positioning of the conserved MED12 activation helix is required for activation of CDK8 via its T-loop, could explain the frequent occurrence of variants in cancers, as this would directly influence the ability of MED12 to activate CDK8 [8,13]. Step 1: Cyclin C binds to CDK8 and pushes the αC-helix of CDK8 into the "pushed-in" conformation.…”

“…The domain name is derived from a conserved sequence motif LCEWAV. To date, no functions of the LCEWAV domain have been described, although the presence of a number of pathologic variants in this domain ( Figure 2 ) suggests that it might have some undiscovered function [ 8 ].…”

“…The paralogs are mutually exclusive with each other, but not with other kinase subunits, allowing for eight different kinase modules [ 5 , 6 , 7 ]. The different kinase modules are cell type-specific, as MED12 and MED13 are ubiquitously expressed [ 8 ], whereas MED13L is mostly expressed in brain and heart tissue [ 9 ], and MED12L is mostly expressed in the brain [ 10 ]. CDK8 and CDK19 seem to have similar expression patterns and are also ubiquitously expressed [ 11 , 12 ].…”

“…MED12 interacts with DNA-bound transcription factors and hence acts as a hub for the communication of transcription factors with the kinase subunit and core Mediator [ 8 ]. It also regulates the activity of the kinase module via interaction with a conserved T-loop on CDK8 [ 13 ].…”

“…It also regulates the activity of the kinase module via interaction with a conserved T-loop on CDK8 [ 13 ]. Due to the important role of MED12 in the regulation of several developmental and signaling pathways, somatic variants in MED12 are known to be involved in cancer and germline variants cause a spectrum of developmental disorders that involve Hardikar syndrome to relatively unspecific non-syndromic intellectual disability (ID) [ 8 , 14 , 15 , 16 ].…”