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Mediator kinase module and human tumorigenesis.
Crit Rev Biochem Mol Biol. 2015; 50(5):393-426.CR

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.

Authors+Show Affiliations

a Department of Molecular Medicine , Institute of Biotechnology, University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.a Department of Molecular Medicine , Institute of Biotechnology, University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.a Department of Molecular Medicine , Institute of Biotechnology, University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

26182352

Citation

Clark, Alison D., et al. "Mediator Kinase Module and Human Tumorigenesis." Critical Reviews in Biochemistry and Molecular Biology, vol. 50, no. 5, 2015, pp. 393-426.
Clark AD, Oldenbroek M, Boyer TG. Mediator kinase module and human tumorigenesis. Crit Rev Biochem Mol Biol. 2015;50(5):393-426.
Clark, A. D., Oldenbroek, M., & Boyer, T. G. (2015). Mediator kinase module and human tumorigenesis. Critical Reviews in Biochemistry and Molecular Biology, 50(5), 393-426. https://doi.org/10.3109/10409238.2015.1064854
Clark AD, Oldenbroek M, Boyer TG. Mediator Kinase Module and Human Tumorigenesis. Crit Rev Biochem Mol Biol. 2015;50(5):393-426. PubMed PMID: 26182352.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mediator kinase module and human tumorigenesis. AU - Clark,Alison D, AU - Oldenbroek,Marieke, AU - Boyer,Thomas G, Y1 - 2015/07/16/ PY - 2015/7/17/entrez PY - 2015/7/17/pubmed PY - 2016/7/28/medline KW - Cancer KW - Mediator KW - RNA polymerase II transcription KW - development KW - signal transduction SP - 393 EP - 426 JF - Critical reviews in biochemistry and molecular biology JO - Crit Rev Biochem Mol Biol VL - 50 IS - 5 N2 - 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. SN - 1549-7798 UR - https://www.unboundmedicine.com/medline/citation/26182352/Mediator_kinase_module_and_human_tumorigenesis_ L2 - https://www.tandfonline.com/doi/full/10.3109/10409238.2015.1064854 DB - PRIME DP - Unbound Medicine ER -