{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T12:23:31Z","timestamp":1772367811538,"version":"3.50.1"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,3,30]],"date-time":"2016-03-30T00:00:00Z","timestamp":1459296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","award":["15K08348"],"award-info":[{"award-number":["15K08348"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We have previously reported that Salvador homologue 1 (<jats:italic><jats:styled-content style=\"fixed-case\">SAV1<\/jats:styled-content><\/jats:italic>), a component of the Hippo pathway, is significantly down\u2010regulated in high\u2010grade clear cell renal cell carcinoma (<jats:styled-content style=\"fixed-case\">ccRCC<\/jats:styled-content>) due to 14q copy number loss, and that this down\u2010regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes\u2010associated protein 1 (<jats:styled-content style=\"fixed-case\">YAP1<\/jats:styled-content>), a downstream target of the Hippo pathway. However, the impact of <jats:italic><jats:styled-content style=\"fixed-case\">SAV1<\/jats:styled-content><\/jats:italic> loss on the proliferation and survival of kidney cells <jats:italic>in vivo<\/jats:italic> remained to be determined. To address this issue, we generated kidney\u2010specific <jats:italic>Sav1<\/jats:italic>\u2010knockout (<jats:italic>Cdh16\u2010<\/jats:italic>Cre;<jats:italic>Sav1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic>) mice. <jats:italic>Sav1<\/jats:italic> deficiency enhanced the proliferation of renal tubular epithelial cells in <jats:italic>Cdh16\u2010<\/jats:italic>Cre;<jats:italic>Sav1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. <jats:italic>Sav1<\/jats:italic> deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, <jats:italic>Cdh16\u2010<\/jats:italic>Cre;<jats:italic>Sav1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged <jats:italic>Cdh16\u2010<\/jats:italic>Cre;<jats:italic>Sav1<jats:sup>fl\/fl<\/jats:sup><\/jats:italic> mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, <jats:italic>Sav1<\/jats:italic> is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling. Copyright \u00a9 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4706","type":"journal-article","created":{"date-parts":[[2016,2,25]],"date-time":"2016-02-25T22:35:56Z","timestamp":1456439756000},"page":"97-108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Kidney\u2010specific knockout of <i>Sav1<\/i> in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway"],"prefix":"10.1002","volume":"239","author":[{"given":"Tomoki","family":"Kai","sequence":"first","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"},{"name":"Department of Urology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Hijiya","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Tokunaga","sequence":"additional","affiliation":[{"name":"Section of Physiology, Department of Integrative Aging Neuroscience National Center for Geriatrics and Gerontology  Obu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chisato","family":"Nakada","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohisa","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Daa","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidekatsu","family":"Iha","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"},{"name":"Department of Urology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Nomura","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuminori","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromitsu","family":"Mimata","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Animal Resource Center for Infectious Diseases Research Institute for Microbial Diseases  Suita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Seto","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine Aichi Cancer Institute  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"},{"name":"Department of Biology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatsugu","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Faculty of Medicine Oita University  Yufu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,3,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2006.06.009"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-198210000-00007"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2239"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-11-523"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2014.02.005"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.210773.112"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.03.003"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912203107"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.63"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1978810"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(197204)29:4<977::AID-CNCR2820290444>3.0.CO;2-P"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.55.137"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2006.09.006"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000016443.50138.CD"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623312438736"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623311431948"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/01926230500299716"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00045.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204692"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8493574"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.197"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-3241"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1745"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201202231"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414789111"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.08.014"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9357"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.037"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911427107"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2007.10.039"},{"key":"e_1_2_7_32_1","article-title":"YAP activation protects urothelial cell carcinoma from treatment\u2010induced DNA damage","author":"Ciamporcero E","year":"2015","journal-title":"Oncogene"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.206"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2013.08.006"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4706","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4706","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/api.wiley.com\/onlinelibrary\/chorus\/v1\/articles\/10.1002%2Fpath.4706","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4706","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:17:27Z","timestamp":1760951847000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4706"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,30]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,5]]}},"alternative-id":["10.1002\/path.4706"],"URL":"https:\/\/doi.org\/10.1002\/path.4706","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,30]]},"assertion":[{"value":"2015-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-02-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-03-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}