{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:39:44Z","timestamp":1790743184329,"version":"4.1.0"},"reference-count":56,"publisher":"Rockefeller University Press","issue":"7","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1998,12,28]]},"abstract":"<jats:p>Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8\/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8\/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that overexpress a human genomic K18 ser52\u2192 ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18-expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.<\/jats:p>","DOI":"10.1083\/jcb.143.7.2023","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:45:41Z","timestamp":1027701941000},"page":"2023-2032","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":88,"title":["Mutation of a Major Keratin Phosphorylation Site Predisposes to Hepatotoxic Injury in Transgenic Mice"],"prefix":"10.1083","volume":"143","author":[{"given":"Nam-On","family":"Ku","sequence":"first","affiliation":[{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"},{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara A.","family":"Michie","sequence":"additional","affiliation":[{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"},{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy M.","family":"Soetikno","sequence":"additional","affiliation":[{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"},{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn Z.","family":"Resurreccion","sequence":"additional","affiliation":[{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"},{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary L.","family":"Broome","sequence":"additional","affiliation":[{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"},{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Bishr","family":"Omary","sequence":"additional","affiliation":[{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"},{"name":"*Department of Medicine, \u2021Department of Pathology, and \u00a7Department of Veterinary Medicine, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304; and the \u2016Digestive Disease Center, Stanford University School of Medicine, Palo Alto, California 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1998,12,28]]},"reference":[{"key":"2023072900505533400_B1","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1083\/jcb.111.3.1197","article-title":"A single human keratin 18 gene is expressed in diverse epithelial cells of transgenic 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