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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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CDK8 and MED12 knockdown in R1 mouse ES cells

ABSTRACT: Transcriptional profiling of R1 mouse ES cells infected with non-targeting control (NTC) shRNA and two different shRNA sequences against Cdk8 (shCdk8-1 and shCdk-2) and Med12 (shMed12-1 and shMed12-2). Multi-condition experiment comparing shNTC versus shCdk8-1 and shCdk8-2 after 8 days (3 biological replicates each) and shNTC versus shCdk8-1, shCdk8-2, shMed12-1, and shMed12-2 after 13 days (3 biological replicates each); in total 24 samples profiled.

ORGANISM(S): Mus musculus

SUBMITTER: Adam Adler

PROVIDER: E-GEOD-30816 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency.

Adler Adam S AS McCleland Mark L ML Truong Tom T Lau Shari S Modrusan Zora Z Soukup Tim M TM Roose-Girma Merone M Blackwood Elizabeth M EM Firestein Ron R

Cancer research 20120216 8

CDK8 is a cyclin-dependent kinase that mediates transcriptional control of pathways linked to both cancer and stem cells. In this study, we show that CDK8 is required for both tumor growth and maintenance of tumor dedifferentiation in vivo and uncover a common role for CDK8 in controlling cancer and stem cell function. Acute CDK8 loss in vivo strongly inhibited tumor growth and promoted differentiation. Transcriptional profiling identified a set of embryonic stem cell-related genes that are acti ...[more]

PMID: 22345154

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CDK8 knockdown in HT-29 cells and CDK8 & MED12 knockdown in R1 cells

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A precisely positioned MED12 activation helix stimulates CDK8 kinase activity

Project description:The Mediator kinase module regulates eukaryotic transcription by phosphorylating transcription-related targets and by modulating the association of Mediator and RNA Polymerase II. The activity of its catalytic core, cyclin-dependent kinase 8 (CDK8), is controlled by Cyclin C and MED12, with its deregulation contributing to numerous malignancies. Here, we combine in vitro biochemistry, crosslinking coupled to mass spectrometry and in vivo studies to describe the binding location of the N-terminal segment of MED12 on the CDK8/Cyclin C complex and to gain mechanistic insights into the activation of CDK8 by MED12. Our data demonstrate that the N-terminal portion of MED12 wraps around CDK8, whereby it positions an "activation helix" close to the T-loop of CDK8 for its activation. Intriguingly, mutations in the activation helix that are frequently found in cancers do not diminish the affinity of MED12 for CDK8, yet likely alter the exact positioning of the activation helix. Furthermore, we find the transcriptome-wide gene expression changes in human cells that result from a mutation in the MED12 activation helix to correlate with deregulated genes in breast and colon cancer. Last, functional assays in presence of kinase inhibitors reveal that binding of MED12 remodels the active site of CDK8 and thereby precludes the inhibition of ternary CDK8 complexes by type-II kinase inhibitors. Taken together, our results not only allow us to propose a revised model of how CDK8 activity is regulated by MED12, but they also offer a path forward in developing small molecules that target CDK8 in its MED12-bound form.

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