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Downregulation of MED12 via siRNA in SPHEROIDS derived from prostate cancer cell lines (3’ tag DGE)

ABSTRACT: The Mediator complex is a multi-subunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase 8 (CDK8) or its paralog CDK19 are components of its kinase module that regulate the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and enzalutamide resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269073 | GEO | 2024/09/26

REPOSITORIES: GEO

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Downregulation of MED12 via siRNA in prostate cancer cell lines (3’ tag DGE)

Project description:The Mediator complex is a multi-subunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase 8 (CDK8) or its paralog CDK19 are components of its kinase module that regulate the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and enzalutamide resistance.

2024-09-26 | GSE269072 | GEO

Downregulation of MED12 via siRNA in 22Rv1 prostate cancer cells (full transcriptome)

2024-09-26 | GSE269070 | GEO

Inhibition of CDK8/CDK19 with the small molecule inhibitor SEL120-34A in prostate cancer cell lines (3’ tag DGE)

2024-09-26 | GSE269071 | GEO

Interactions of CDK19 with MED12 and cyclin-C assessed by chemical cross-linking mass spectrometry

Project description:Chemical cross-linking coupled to mass spectrometry was used to study binary and ternary complexes involving cyclin-dependent kinase 19 (CDK19), cyclin-C, and an N-terminal fragment of subunit 12 of the Mediator complex (MED12 1-100). Cross-linking was performed using disuccinimidyl suberate (DSS). These results were generated in the context of the study published as Klatt et al., A precisely positioned MED12 activation helix stimulates CDK8 kinase activity, Proc. Natl. Acad. Sci. USA 2020 (DOI: 10.1073/pnas.1917635117) with the associated data set PXD015394, but were not included in the article.

2020-05-18 | PXD019251 | Pride

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.

2020-01-04 | GSE135458 | GEO

Requirement for the Mediator kinase module for activation of super-enhancer associated genes in colon cancer cells

Project description:RNA sequencing of HCT116 colon cancer cells following single and combined depletions of Mediator kinase module subunits CDK8, CDK19, MED12, MED13 and MED13L and the BET family protein BRD4. The results provide insight into the shared and specific functions of kinase module subunits and BRD4 in regulation of expression of transcriptional programs including genes associated with cancer acquired super-enhancers.

2018-04-02 | E-MTAB-5873 | biostudies-arrayexpress

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

Project description:This SuperSeries is composed of the following subset Series: GSE30815: CDK8 knockdown in HT-29 human colon cancer cells GSE30816: CDK8 and MED12 knockdown in R1 mouse ES cells Refer to individual Series

2012-03-05 | E-GEOD-30817 | biostudies-arrayexpress

Cdk8, Cyclin C, Med12 or Med13 depletion effect on gene expression in Drosophila S2 cells

Project description:Expression profiling following depletion of Mediator Cdk8 module subunits Cdk8, Cyclin C (CycC), Med12 and Med13 72 hours after dsRNA treatment of Drosophila melanogaster S2 cells. Results provide insight into the role of individual Cdk8 module subunits in regulation of transcription. 22 samples. 2 Cdk8 dsRNA, 4 CycC dsRNA, 4 Med12 dsRNA, 4 Med13 dsRNA, 8 control samples including 4 Luciferase (Luc) dsRNA and 4 GFP dsRNA

2014-04-29 | E-GEOD-52343 | biostudies-arrayexpress

A precisely positioned MED12 activation helix stimulates CDK8 kinase activity

Project description:Chemical cross-linking coupled to mass spectrometry was used to study binary and ternary complexes involving cyclin-dependent kinase 8 (CDK8), cyclin-C, and subunit 12 of the Mediator complex (MED12). Cross-linking was performed using different cross-linking chemistries: (1) disuccinimidyl suberate (DSS); (2) a combination of pimelic acid dihydrazide (PDH) and the coupling reagent, DMTMM.

2020-01-16 | PXD015394 | Pride

Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase [ChIP]

Project description:Depletion of CDK8 and its paralogue CDK19, resulted in a global down regulation of mRNA expression, and hence we went to investigate the binding of RNA pol II by ChIP seq at the promoter and at the gene body in the DKO cells. To determine the consequence of loss of CDK8/19 in re-defining enhancers and to underpin the molecular mechanism that providing the preferential BET sensitivity for DKO, we performed ChIP sequencing for MED12, a reminiscent mediator kinase component, BRD4 and H3K27Ac. We identified that MED12 redefines the enhancer landscape in the absence of CDK8/19, recruit BRD4 at the cis regions and can be targeted using BET inhibitors

2021-12-28 | GSE163755 | GEO

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