Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jan 14:6:171.
doi: 10.3389/fcell.2018.00171. eCollection 2018.

Molecular and in vivo Functions of the CDK8 and CDK19 Kinase Modules

Marius Volker Dannappel  1   2 , Dhanya Sooraj  1   2 , Jia Jian Loh  1   3 , Ron Firestein  1   2
Affiliations
Review

Molecular and in vivo Functions of the CDK8 and CDK19 Kinase Modules

Marius Volker Dannappel et al. Front Cell Dev Biol. .

Abstract

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 signaling, 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: CDK19; Cdk8; cyclin-depedent kinase; development; developmental signaling; mediator kinase; mouse models; tissue homeostasis.

PubMed Disclaimer

References

    1. Adler A. S., McCleland M. L., Truong T., Lau S., Modrusan Z., Soukup T. M., et al. (2012). CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. Cancer Res. 72 2129–2139. 10.1158/0008-5472.CAN-11-3886 - DOI - PubMed
    1. Alarcón C., Zaromytidou A. I., Xi Q., Gao S., Yu J., Fujisawa S., et al. (2009). Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139 757–769. 10.1016/j.cell.2009.09.035 - DOI - PMC - PubMed
    1. Allen B. L., Taatjes D. J. (2015). The mediator complex: a central integrator of transcription. Nat. Rev. Mol. Cell Biol. 16 155–166. 10.1038/nrm3951 - DOI - PMC - PubMed
    1. Aranda-Orgilles B., Saldaña-Meyer R., Wang E., Trompouki E., Fassl A., Lau S., et al. (2016). MED12 regulates HSC-specific enhancers independently of mediator kinase activity to control hematopoiesis. Cell Stem Cell 19 784–799. 10.1016/j.stem.2016.08.004 - DOI - PMC - PubMed
    1. Asadollahi R., Oneda B., Sheth F., Azzarello-Burri S., Baldinger R., Joset P., et al. (2013). Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability. Eur. J. Hum. Genet. 21 1100–1104. 10.1038/ejhg.2013.17 - DOI - PMC - PubMed