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CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins
We have conducted a detailed transcriptomic, proteomic and phosphoproteomic analysis of CDK8 and its paralog CDK19, alternative enzymatic components of the kinase module associated with transcriptional Mediator complex and implicated in development and diseases. This analysis was performed using gen...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415139/ https://www.ncbi.nlm.nih.gov/pubmed/37378433 http://dx.doi.org/10.1093/nar/gkad538 |
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author | Chen, Mengqian Li, Jing Zhang, Li Wang, Lili Cheng, Chen Ji, Hao Altilia, Serena Ding, Xiaokai Cai, Guoshuai Altomare, Diego Shtutman, Michael Byrum, Stephanie D Mackintosh, Samuel G Feoktistov, Alexey Soshnikova, Nataliya Mogila, Vladislav A Tatarskiy, Victor Erokhin, Maksim Chetverina, Darya Prawira, Angga Ni, Yi Urban, Stephan McInnes, Campbell Broude, Eugenia V Roninson, Igor B |
author_facet | Chen, Mengqian Li, Jing Zhang, Li Wang, Lili Cheng, Chen Ji, Hao Altilia, Serena Ding, Xiaokai Cai, Guoshuai Altomare, Diego Shtutman, Michael Byrum, Stephanie D Mackintosh, Samuel G Feoktistov, Alexey Soshnikova, Nataliya Mogila, Vladislav A Tatarskiy, Victor Erokhin, Maksim Chetverina, Darya Prawira, Angga Ni, Yi Urban, Stephan McInnes, Campbell Broude, Eugenia V Roninson, Igor B |
author_sort | Chen, Mengqian |
collection | PubMed |
description | We have conducted a detailed transcriptomic, proteomic and phosphoproteomic analysis of CDK8 and its paralog CDK19, alternative enzymatic components of the kinase module associated with transcriptional Mediator complex and implicated in development and diseases. This analysis was performed using genetic modifications of CDK8 and CDK19, selective CDK8/19 small molecule kinase inhibitors and a potent CDK8/19 PROTAC degrader. CDK8/19 inhibition in cells exposed to serum or to agonists of NFκB or protein kinase C (PKC) reduced the induction of signal-responsive genes, indicating a pleiotropic role of Mediator kinases in signal-induced transcriptional reprogramming. CDK8/19 inhibition under basal conditions initially downregulated a small group of genes, most of which were inducible by serum or PKC stimulation. Prolonged CDK8/19 inhibition or mutagenesis upregulated a larger gene set, along with a post-transcriptional increase in the proteins comprising the core Mediator complex and its kinase module. Regulation of both RNA and protein expression required CDK8/19 kinase activities but both enzymes protected their binding partner cyclin C from proteolytic degradation in a kinase-independent manner. Analysis of isogenic cell populations expressing CDK8, CDK19 or their kinase-inactive mutants revealed that CDK8 and CDK19 have the same qualitative effects on protein phosphorylation and gene expression at the RNA and protein levels, whereas differential effects of CDK8 versus CDK19 knockouts were attributable to quantitative differences in their expression and activity rather than different functions. |
format | Online Article Text |
id | pubmed-10415139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-104151392023-08-12 CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins Chen, Mengqian Li, Jing Zhang, Li Wang, Lili Cheng, Chen Ji, Hao Altilia, Serena Ding, Xiaokai Cai, Guoshuai Altomare, Diego Shtutman, Michael Byrum, Stephanie D Mackintosh, Samuel G Feoktistov, Alexey Soshnikova, Nataliya Mogila, Vladislav A Tatarskiy, Victor Erokhin, Maksim Chetverina, Darya Prawira, Angga Ni, Yi Urban, Stephan McInnes, Campbell Broude, Eugenia V Roninson, Igor B Nucleic Acids Res Gene regulation, Chromatin and Epigenetics We have conducted a detailed transcriptomic, proteomic and phosphoproteomic analysis of CDK8 and its paralog CDK19, alternative enzymatic components of the kinase module associated with transcriptional Mediator complex and implicated in development and diseases. This analysis was performed using genetic modifications of CDK8 and CDK19, selective CDK8/19 small molecule kinase inhibitors and a potent CDK8/19 PROTAC degrader. CDK8/19 inhibition in cells exposed to serum or to agonists of NFκB or protein kinase C (PKC) reduced the induction of signal-responsive genes, indicating a pleiotropic role of Mediator kinases in signal-induced transcriptional reprogramming. CDK8/19 inhibition under basal conditions initially downregulated a small group of genes, most of which were inducible by serum or PKC stimulation. Prolonged CDK8/19 inhibition or mutagenesis upregulated a larger gene set, along with a post-transcriptional increase in the proteins comprising the core Mediator complex and its kinase module. Regulation of both RNA and protein expression required CDK8/19 kinase activities but both enzymes protected their binding partner cyclin C from proteolytic degradation in a kinase-independent manner. Analysis of isogenic cell populations expressing CDK8, CDK19 or their kinase-inactive mutants revealed that CDK8 and CDK19 have the same qualitative effects on protein phosphorylation and gene expression at the RNA and protein levels, whereas differential effects of CDK8 versus CDK19 knockouts were attributable to quantitative differences in their expression and activity rather than different functions. Oxford University Press 2023-06-28 /pmc/articles/PMC10415139/ /pubmed/37378433 http://dx.doi.org/10.1093/nar/gkad538 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Gene regulation, Chromatin and Epigenetics Chen, Mengqian Li, Jing Zhang, Li Wang, Lili Cheng, Chen Ji, Hao Altilia, Serena Ding, Xiaokai Cai, Guoshuai Altomare, Diego Shtutman, Michael Byrum, Stephanie D Mackintosh, Samuel G Feoktistov, Alexey Soshnikova, Nataliya Mogila, Vladislav A Tatarskiy, Victor Erokhin, Maksim Chetverina, Darya Prawira, Angga Ni, Yi Urban, Stephan McInnes, Campbell Broude, Eugenia V Roninson, Igor B CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins |
title | CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins |
title_full | CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins |
title_fullStr | CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins |
title_full_unstemmed | CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins |
title_short | CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins |
title_sort | cdk8 and cdk19: positive regulators of signal-induced transcription and negative regulators of mediator complex proteins |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415139/ https://www.ncbi.nlm.nih.gov/pubmed/37378433 http://dx.doi.org/10.1093/nar/gkad538 |
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