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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\u2010term proliferative capacity but is not lethal and allows differentiation. However, double\u2010mutant 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.<\/jats:p>","DOI":"10.15252\/embr.202154261","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T03:14:16Z","timestamp":1671678856000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9746-2396","authenticated-orcid":false,"given":"Susana","family":"Prieto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9486-3274","authenticated-orcid":false,"given":"Geronimo","family":"Dubra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Camasses","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7024-7189","authenticated-orcid":false,"given":"Ana Bella","family":"Aznar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0508-6013","authenticated-orcid":false,"given":"Christina","family":"Begon\u2010Pescia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Simboeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Pirot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Gerbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Angevin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Jay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6858-0852","authenticated-orcid":false,"given":"Liliana","family":"Krasinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0822-3482","authenticated-orcid":false,"given":"Daniel","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"BFEMBR202154261_CR1","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1158\/0008-5472.CAN-11-3886","volume":"72","author":"AS Adler","year":"2012","unstructured":"Adler AS, McCleland ML, Truong T, Lau S, Modrusan Z, Soukup TM, Roose\u2010Girma M, Blackwood EM, Firestein R (2012) CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. 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