CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium
Susana Prieto
(1, 2)
,
Geronimo Dubra
(1, 2)
,
Alain Camasses
(1, 2)
,
Ana Bella Aznar
(1, 2)
,
Christina Begon-Pescia
(1)
,
Elisabeth Simboeck
(1, 2)
,
Nelly Pirot
(3, 4, 5)
,
François Gerbe
(6, 2)
,
Lucie Angevin
(1, 2)
,
Philippe Jay
(2, 6)
,
Liliana Krasinska
(1, 2)
,
Daniel Fisher
(1, 2)
1
IGMM -
Institut de Génétique Moléculaire de Montpellier
2 LNCC - Ligue Nationale Contre le Cancer
3 ICM - Institut régional de Cancérologie de Montpellier
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 RHEM - Réseau d'histologie expérimentale de Montpellier
6 IGF - Institut de Génomique Fonctionnelle
2 LNCC - Ligue Nationale Contre le Cancer
3 ICM - Institut régional de Cancérologie de Montpellier
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 RHEM - Réseau d'histologie expérimentale de Montpellier
6 IGF - Institut de Génomique Fonctionnelle
Susana Prieto
- Fonction : Auteur
- PersonId : 14767
- IdHAL : susana-prieto
- ORCID : 0000-0002-9746-2396
Geronimo Dubra
- Fonction : Auteur
- PersonId : 785093
- ORCID : 0000-0002-9486-3274
Christina Begon-Pescia
- Fonction : Auteur
- PersonId : 1209313
- ORCID : 0000-0002-0508-6013
François Gerbe
- Fonction : Auteur
- PersonId : 180066
- IdHAL : francois-gerbe
- ORCID : 0000-0002-5006-8930
- IdRef : 123452554
Philippe Jay
- Fonction : Auteur
- PersonId : 182006
- IdHAL : philippe-jay
- ORCID : 0000-0003-0156-5700
- IdRef : 120996049
Daniel Fisher
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 857332
Connectez-vous pour contacter l'auteur
Résumé
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 du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Résumé |
en
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.
|
Titre |
en
CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium
|
Auteur(s) |
Susana Prieto
1, 2
, Geronimo Dubra
1, 2
, Alain Camasses
1, 2
, Ana Bella Aznar
1, 2
, Christina Begon-Pescia
1
, Elisabeth Simboeck
1, 2
, Nelly Pirot
3, 4, 5
, François Gerbe
6, 2
, Lucie Angevin
1, 2
, Philippe Jay
2, 6
, Liliana Krasinska
1, 2
, Daniel Fisher
1, 2
1
IGMM -
Institut de Génétique Moléculaire de Montpellier
( 1100656 )
- 1919 Route de Mende - 34293 Montpellier Cedex 5
- France
2
LNCC -
Ligue Nationale Contre le Cancer
( 321644 )
- France
3
ICM -
Institut régional de Cancérologie de Montpellier
( 333482 )
- 124-226 Av. des Apothicaires, 34090 Montpellier
- France
4
IRCM - U1194 Inserm - UM -
Institut de Recherche en Cancérologie de Montpellier
( 1100769 )
- Campus Val d’Aurelle - Parc Euromédecine - 208, rue des Apothicaires 34298 Montpellier
- France
5
RHEM -
Réseau d'histologie expérimentale de Montpellier
( 1080577 )
- nstitut de Recherche en Cancérologie de
Montpellier (U1194) - Campus Val d'Aurelle
208 avenue des Apothicaires
34298 Montpellier cedex 5
- France
6
IGF -
Institut de Génomique Fonctionnelle
( 1100822 )
- 141, Rue de la Cardonille 34094 Montpellier cedex 5
- France
|
Date de publication électronique |
2022-12
|
Date de publication |
2023-02
|
Volume |
24
|
Numéro |
2
|
Page/Identifiant |
e54261
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Langue du document |
Anglais
|
Domaine(s) |
|
Mots-clés |
en
CDK19, CDK8, CFTR, intestinal epithelium, Mediator
|
DOI | 10.15252/embr.202154261 |
Pubmed Id | 36545778 |
Fichier principal
CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium Prieto EMBO Reports 2022.pdf ( 7.76 Mo
)
Télécharger
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