Show simple item record

dc.contributor.authorCai, J.
dc.contributor.authorSong, X.
dc.contributor.authorWang, W.
dc.date.accessioned2019-05-21T18:56:21Z
dc.date.available2019-05-21T18:56:21Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85048825501&doi=10.1101%2fgad.315127.118&partnerID=40&md5=b40ce3f99a7bda4db7af3ae96aa882cd
dc.identifier.urihttp://hdl.handle.net/10713/9238
dc.description.abstractAutosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in PKD1 or PKD2 and affects one in 500-1000 humans. Limited treatment is currently available for ADPKD. Here we identify the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. While transgenic overexpression of YAP promotes proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or c-Myc suppresses cystogenesis in a mouse ADPKD model resulting from Pkd1 deficiency. Through a comprehensive kinase inhibitor screen based on a novel three-dimensional (3D) culture of Pkd1 mutant mouse kidney cells, we identified a signaling pathway involving the RhoGEF (guanine nucleotide exchange factor) LARG, the small GTPase RhoA, and the RhoA effector Rho-associated kinase (ROCK) as a critical signaling module between PKD1 and YAP. Further corroborating its physiological importance, inhibition of RhoA signaling suppresses cystogenesis in 3D culture of Pkd1 mutant kidney cells as well as Pkd1 mutant mouse kidneys in vivo. Taken together, our findings implicate the RhoA-YAP-c-Myc signaling axis as a critical mediator and potential drug target in ADPKD. Copyright 2018 Cai et al.en_US
dc.description.sponsorshipThis study was supported in part by grants from the Department of Defense (PR130920) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK098424, DK095036, and DK111611). This work was supported by a pilot grant from the Baltimore Polycystic Kidney Disease Research and Clinical Core Center (P30 DK090868).en_US
dc.description.urihttps://dx.doi.org/10.1101/gad.315127.118en_US
dc.language.isoen_USen_US
dc.publisherCold Spring Harbor Laboratory Pressen_US
dc.relation.ispartofGenes and Development
dc.subject3D cultureen_US
dc.subjectADPKDen_US
dc.subjectC-Mycen_US
dc.subjectHippo signalingen_US
dc.subjectRhoA signalingen_US
dc.subjectYAP/TAZen_US
dc.titleA RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney diseaseen_US
dc.typeArticleen_US
dc.identifier.doi10.1101/gad.315127.118
dc.identifier.pmid29891559


This item appears in the following Collection(s)

Show simple item record