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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.
Afiliación
  • Prieto S; IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
  • Dubra G; Equipe Labellisée LIGUE 2018, Ligue Nationale Contre le Cancer, Paris, France.
  • Camasses A; IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
  • Aznar AB; Equipe Labellisée LIGUE 2018, Ligue Nationale Contre le Cancer, Paris, France.
  • Begon-Pescia C; IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
  • Simboeck E; Equipe Labellisée LIGUE 2018, Ligue Nationale Contre le Cancer, Paris, France.
  • Pirot N; IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
  • Gerbe F; Equipe Labellisée LIGUE 2018, Ligue Nationale Contre le Cancer, Paris, France.
  • Angevin L; IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
  • Jay P; IGMM, University of Montpellier, CNRS, Inserm, Montpellier, France.
  • Krasinska L; Equipe Labellisée LIGUE 2018, Ligue Nationale Contre le Cancer, Paris, France.
  • Fisher D; IRCM, University of Montpellier, ICM, INSERM, Montpellier, France.
EMBO Rep ; 24(2): e54261, 2023 02 06.
Article en En | MEDLINE | ID: mdl-36545778
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Transducción de Señal / Quinasas Ciclina-Dependientes / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Mucosa Intestinal Límite: Animals Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Transducción de Señal / Quinasas Ciclina-Dependientes / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Mucosa Intestinal Límite: Animals Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Francia