ArticleProceedings of the National Academy of Sciences of the United States of America2020
A precisely positioned MED12 activation helix stimulates CDK8 kinase activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 74 citations in OpenAlex.
- An Experimentally Validated Structure-Based Virtual Screening Approach to Identify Nucleotide-Binding Protein Inhibitors as a New Source of Kinase Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Molecular pathology of phyllodes tumours of the breast-much more than MED12.Histopathology · 2026Review
- The Mediator Complex: From Transcriptional Regulation to Disease Pathogenesis.International journal of molecular sciences · 2026Review
- Therapeutic potential of CDK8 inhibitor combined with sorafenib for hepatocellular carcinoma: mechanistic insights and in vitro validation.European journal of medical research · 2026Article
- Improving the Accumulation and Solubility of Human Interferon-γ (hIFN-γ) in Escherichia coli: A Fusion Protein-Based Method and Network Pharmacology Analysis.Applied biochemistry and biotechnology · 2025Article
- Epigenetic regulation of MED12: a key contributor to the leukemic chromatin landscape and transcriptional dysregulation.Epigenetics & chromatin · 2025Article
- A highly sensitive protein-RNA cross-linking mass spectrometry workflow with enhanced structural modeling potential.Nucleic acids research · 2025Article
- The Mediator Kinase Module regulates cell cycle re-entry and transcriptional responses following DNA damage.bioRxiv : the preprint server for biology · 2025Article
- The Cyclin-Dependent Kinase 8 Inhibitor E966-0530-45418 Attenuates Pulmonary FibrosisInternational journal of biological sciences · 2025Article
- Distinct effects of CDK8 module subunits on cellular growth and proliferation in Drosophila.Development (Cambridge, England) · 2024Article
- Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module.Molecular cell · 2024Article
- Structures and compositional dynamics of Mediator in transcription regulation.Current opinion in structural biology · 2024Review
- Hypoxia in uterine fibroids: role in pathobiology and therapeutic opportunities.Oxygen (Basel, Switzerland) · 2024Article
- The Mediator kinase module enhances polymerase activity to regulate transcriptional memory after heat stress in Arabidopsis.The EMBO journal · 2024Article
- Novel pathogenic variant in MED12 causing non-syndromic dilated cardiomyopathy.BMC medical genomics · 2023Article
- MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas.JCI insight · 2023Article
- Emerging approaches to CDK inhibitor development, a structural perspective.RSC chemical biology · 2023Article
- Towards a structurally resolved human protein interaction network.Nature structural & molecular biology · 2023Article
- Computational Exploration of Anti-cancer Potential of Flavonoids against Cyclin-Dependent Kinase 8: AnACS omega · 2023Article
- Unveiling the noncanonical activation mechanism of CDKs: insights from recent structural studies.Frontiers in molecular biosciences · 2023Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 regulatory subunit MED12, with its deregulation contributing to numerous malignancies. Here, we combine in vitro biochemistry, cross-linking 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. Finally, functional assays in the 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 also offer a path forward in developing small molecules that target CDK8 in its MED12-bound form.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.