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CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium
CDK8 and CDK19 form a conserved cyclin‐dependent kinase subfamily that interacts with the essential transcription complex, Mediator, and also phosphorylates the C‐terminal domain of RNA polymerase II. Cells lacking either CDK8 or CDK19 are viable and have limited transcriptional alterations, but whe...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10549226/ https://www.ncbi.nlm.nih.gov/pubmed/36545778 http://dx.doi.org/10.15252/embr.202154261 |
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author | Prieto, Susana Dubra, Geronimo Camasses, Alain Aznar, Ana Bella Begon‐Pescia, Christina Simboeck, Elisabeth Pirot, Nelly Gerbe, François Angevin, Lucie Jay, Philippe Krasinska, Liliana Fisher, Daniel |
author_facet | Prieto, Susana Dubra, Geronimo Camasses, Alain Aznar, Ana Bella Begon‐Pescia, Christina Simboeck, Elisabeth Pirot, Nelly Gerbe, François Angevin, Lucie Jay, Philippe Krasinska, Liliana Fisher, Daniel |
author_sort | Prieto, Susana |
collection | PubMed |
description | CDK8 and CDK19 form a conserved cyclin‐dependent kinase subfamily that interacts with the essential transcription complex, Mediator, and also phosphorylates the C‐terminal domain of RNA polymerase II. Cells lacking either CDK8 or CDK19 are viable and have limited transcriptional alterations, but whether the two kinases redundantly control cell proliferation and differentiation is unknown. Here, we find in mice that CDK8 is dispensable for regulation of gene expression, normal intestinal homeostasis, and efficient tumourigenesis, and is largely redundant with CDK19 in the control of gene expression. Their combined deletion in intestinal organoids reduces long‐term proliferative capacity but is not lethal and allows differentiation. However, double‐mutant organoids show mucus accumulation and increased secretion by goblet cells, as well as downregulation of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and functionality of the CFTR pathway. Pharmacological inhibition of CDK8/19 kinase activity in organoids and in mice recapitulates several of these phenotypes. Thus, the Mediator kinases are not essential for cell proliferation and differentiation in an adult tissue, but they cooperate to regulate specific transcriptional programmes. |
format | Online Article Text |
id | pubmed-10549226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105492262023-10-05 CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium Prieto, Susana Dubra, Geronimo Camasses, Alain Aznar, Ana Bella Begon‐Pescia, Christina Simboeck, Elisabeth Pirot, Nelly Gerbe, François Angevin, Lucie Jay, Philippe Krasinska, Liliana Fisher, Daniel EMBO Rep Articles CDK8 and CDK19 form a conserved cyclin‐dependent kinase subfamily that interacts with the essential transcription complex, Mediator, and also phosphorylates the C‐terminal domain of RNA polymerase II. Cells lacking either CDK8 or CDK19 are viable and have limited transcriptional alterations, but whether the two kinases redundantly control cell proliferation and differentiation is unknown. Here, we find in mice that CDK8 is dispensable for regulation of gene expression, normal intestinal homeostasis, and efficient tumourigenesis, and is largely redundant with CDK19 in the control of gene expression. Their combined deletion in intestinal organoids reduces long‐term proliferative capacity but is not lethal and allows differentiation. However, double‐mutant organoids show mucus accumulation and increased secretion by goblet cells, as well as downregulation of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and functionality of the CFTR pathway. Pharmacological inhibition of CDK8/19 kinase activity in organoids and in mice recapitulates several of these phenotypes. Thus, the Mediator kinases are not essential for cell proliferation and differentiation in an adult tissue, but they cooperate to regulate specific transcriptional programmes. John Wiley and Sons Inc. 2022-12-22 /pmc/articles/PMC10549226/ /pubmed/36545778 http://dx.doi.org/10.15252/embr.202154261 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Prieto, Susana Dubra, Geronimo Camasses, Alain Aznar, Ana Bella Begon‐Pescia, Christina Simboeck, Elisabeth Pirot, Nelly Gerbe, François Angevin, Lucie Jay, Philippe Krasinska, Liliana Fisher, Daniel CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium |
title | CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium |
title_full | CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium |
title_fullStr | CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium |
title_full_unstemmed | CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium |
title_short | CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium |
title_sort | cdk8 and cdk19 act redundantly to control the cftr pathway in the intestinal epithelium |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10549226/ https://www.ncbi.nlm.nih.gov/pubmed/36545778 http://dx.doi.org/10.15252/embr.202154261 |
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