{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T06:46:24Z","timestamp":1785825984783,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009711","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000}}],"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"national institute of diabetes and digestive and kidney diseases","doi-asserted-by":"publisher","award":["DK103632"],"award-info":[{"award-number":["DK103632"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"national institute of diabetes and digestive and kidney diseases","doi-asserted-by":"publisher","award":["DK107220"],"award-info":[{"award-number":["DK107220"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of\n                    <jats:italic>Pkd<\/jats:italic>\n                    mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by\n                    <jats:italic>Pkd2<\/jats:italic>\n                    loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of\n                    <jats:italic>Jnk1<\/jats:italic>\n                    and\n                    <jats:italic>Jnk2<\/jats:italic>\n                    suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While\n                    <jats:italic>Jnk1<\/jats:italic>\n                    and\n                    <jats:italic>Jnk2<\/jats:italic>\n                    are thought to have largely overlapping functions, we find that\n                    <jats:italic>Jnk1<\/jats:italic>\n                    loss is nearly as effective as the double loss of\n                    <jats:italic>Jnk1<\/jats:italic>\n                    and\n                    <jats:italic>Jnk2<\/jats:italic>\n                    . Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009711","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T14:46:30Z","timestamp":1640702790000},"page":"e1009711","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2765-8737","authenticated-orcid":true,"given":"Abigail O.","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Jonassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-0878","authenticated-orcid":true,"given":"Kenley M.","family":"Preval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0130-1652","authenticated-orcid":true,"given":"Roger J.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-8796","authenticated-orcid":true,"given":"Gregory J.","family":"Pazour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"issue":"6406","key":"pgen.1009711.ref001","article-title":"Structure of the human PKD1-PKD2 complex","volume":"361","author":"Q Su","year":"2018","journal-title":"Science"},{"issue":"10","key":"pgen.1009711.ref002","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1097\/01.ASN.0000141055.57643.E0","article-title":"Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease","volume":"15","author":"GJ Pazour","year":"2004","journal-title":"J Am Soc Nephrol"},{"issue":"9","key":"pgen.1009711.ref003","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/ng.2715","article-title":"Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease","volume":"45","author":"M Ma","year":"2013","journal-title":"Nat Genet"},{"issue":"11","key":"pgen.1009711.ref004","article-title":"Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease.","volume":"9","author":"M Ma","year":"2017","journal-title":"Cold Spring Harb Perspect Biol."},{"issue":"1","key":"pgen.1009711.ref005","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1681\/ASN.2005060645","article-title":"Calcium restores a normal proliferation phenotype in human polycystic kidney disease epithelial cells","volume":"17","author":"T Yamaguchi","year":"2006","journal-title":"J Am Soc Nephrol"},{"issue":"39","key":"pgen.1009711.ref006","doi-asserted-by":"crossref","first-page":"40419","DOI":"10.1074\/jbc.M405079200","article-title":"Calcium restriction allows cAMP activation of the B-Raf\/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype","volume":"279","author":"T Yamaguchi","year":"2004","journal-title":"J Biol Chem"},{"key":"pgen.1009711.ref007","doi-asserted-by":"crossref","unstructured":"Calvet JP. 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