The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function

Knuesel, Matthew T.; Meyer, Krista; Bernecky, Carrie; Taatjes, Dylan J.

doi:10.1101/gad.1767009

Cited by 302 publications

(394 citation statements)

References 54 publications

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“…However, only a fraction of CDK8 binds to MED12 and MED13 in mammalian cells, suggesting that CDK8 can also have Mediator-independent functions. [45][46][47] In addition, although CDK8 module is generally thought to inhibit transcription, the CDK8 kinase activity is not always required for this function for different transactivators. 9 Therefore, the function of CDK8 can be defined as the CDK8 kinase or the transcription function of the CDK8 submodule.…”

Section: Discussionmentioning

confidence: 99%

Tumor-suppressive effects of CDK8 in endometrial cancer cells

Wang

et al. 2013

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

Tumor-suppressive effects of CDK8 in endometrial cancer cells

Wang

et al. 2013

Cell Cycle

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“…The kinase module of the Med complex can repress as well as activate transcription (Taatjes, 2010), where Med12 and Med13 subunits play a critical role for the subcomplex-dependent repression (Knuesel et al, 2009). Med12 promotes the epigenetic silencing of target genes by recruiting a histone methyltransferase and methylating chromatin (Ding et al, 2008).…”

Section: Expression Profile Of the Kinase Module And Other Associatedmentioning

confidence: 99%

The Mediator Complex in Plants: Structure, Phylogeny, and Expression Profiling of Representative Genes in a Dicot (Arabidopsis) and a Monocot (Rice) during Reproduction and Abiotic Stress

et al. 2011

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The Mediator (Med) complex relays regulatory information from DNA-bound transcription factors to the RNA polymerase II in eukaryotes. This macromolecular unit is composed of three core subcomplexes in addition to a separable kinase module. In this study, conservation of Meds has been investigated in 16 plant species representing seven diverse groups across the plant kingdom. Using Hidden Markov Model-based conserved motif searches, we have identified all the known yeast/metazoan Med components in one or more plant groups, including the Med26 subunits, which have not been reported so far for any plant species. We also detected orthologs for the Arabidopsis (Arabidopsis thaliana) Med32, -33, -34, -35, -36, and -37 in all the plant groups, and in silico analysis identified the Med32 and Med33 subunits as apparent orthologs of yeast/metazoan Med2/ 29 and Med5/24, respectively. Consequently, the plant Med complex appears to be composed of one or more members of 34 subunits, as opposed to 25 and 30 members in yeast and metazoans, respectively. Despite low similarity in primary Med sequences between the plants and their fungal/metazoan partners, secondary structure modeling of these proteins revealed a remarkable similarity between them, supporting the conservation of Med organization across kingdoms. Phylogenetic analysis between plant, human, and yeast revealed single clade relatedness for 29 Med genes families in plants, plant Meds being closer to human than to yeast counterparts. Expression profiling of rice (Oryza sativa) and Arabidopsis Med genes reveals that Meds not only act as a basal regulator of gene expression but may also have specific roles in plant development and under abiotic stress conditions.

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“…[30][31][32][33] The Cdk8 module or RNA Polymerase II (Pol II) bind mutually exclusive to Mediator, which likely constitutes a means of regulating Mediator function. 26,30,34,35 Still, the function of the Cdk8 module is under debate since its subunits have been implicated in both, transcriptional activation and repression. 29,[36][37][38][39][40] In particular, Med12 was shown to operate as a signaling pathway hub in C. elegans suggesting a function in different cellular pathways.…”

Section: Introductionmentioning

confidence: 99%

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

et al. 2016

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Mediator is considered an enhancer of RNA-Polymerase II dependent transcription but its function and regulation in pluripotent mouse embryonic stem cells (mESCs) remains unresolved. One means of controlling the function of Mediator is provided by the binding of the Cdk8 module (Med12, Cdk8, Ccnc and Med13) to the core Mediator. Here we report that Med12 operates together with PRC1 to silence key developmental genes in pluripotency. At the molecular level, while PRC1 represses genes it is also required to assemble ncRNA containing Med12-Mediator complexes. In the course of cellular differentiation the H2A ubiquitin binding protein Zrf1 abrogates PRC1-Med12 binding and facilitates the association of Cdk8 with Mediator. This remodeling of Mediator-associated protein complexes converts Mediator from a transcriptional repressor to a transcriptional enhancer, which then mediates ncRNA-dependent activation of Polycomb target genes. Altogether, our data reveal how the interplay of PRC1, ncRNA and Mediator complexes controls pluripotency and cellular differentiation.

show abstract

The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function

Cited by 302 publications

References 54 publications

Tumor-suppressive effects of CDK8 in endometrial cancer cells

Tumor-suppressive effects of CDK8 in endometrial cancer cells

The Mediator Complex in Plants: Structure, Phylogeny, and Expression Profiling of Representative Genes in a Dicot (Arabidopsis) and a Monocot (Rice) during Reproduction and Abiotic Stress

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

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