{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:40:31Z","timestamp":1791268831193,"version":"4.1.0"},"reference-count":54,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,4,13]]},"abstract":"<jats:p>The molecular mechanisms underlying the development of hepatocellular carcinoma are not fully understood. Liver-specific signal transducer and activator of transcription (STAT) 5A\/B\u2013null mice (STAT5-LKO) were treated with carbon tetrachloride (CCl4), and histological analyses revealed liver fibrosis and tumors. Transforming growth factor (TGF)\u2013\u03b2 levels and STAT3 activity were elevated in liver tissue from STAT5-LKO mice upon CCl4 treatment. To define the molecular link between STAT5 silencing and TGF-\u03b2 up-regulation, as well as STAT3 activation, we examined STAT5-null mouse embryonic fibroblasts and primary hepatocytes. These cells displayed elevated TGF-\u03b2 protein levels, whereas messenger RNA levels remained almost unchanged. Protease inhibitor studies revealed that STAT5 deficiency enhanced the stability of mature TGF-\u03b2. Immunoprecipitation and immunohistochemistry analyses demonstrated that STAT5, through its N-terminal sequences, could bind to TGF-\u03b2 and that retroviral-mediated overexpression of STAT5 decreased TGF-\u03b2 levels. To confirm the in vivo significance of the N-terminal domain of STAT5, we treated mice that expressed STAT5 lacking the N terminus (STAT5-\u0394N) with CCl4. STAT5-\u0394N mice developed CCl4-induced liver fibrosis but no tumors. In conclusion, loss of STAT5 results in elevated TGF-\u03b2 levels and enhanced growth hormone\u2013induced STAT3 activity. We propose that a deregulated STAT5\u2013TGF-\u03b2\u2013STAT3 network contributes to the development of chronic liver disease.<\/jats:p>","DOI":"10.1084\/jem.20080003","type":"journal-article","created":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T04:03:48Z","timestamp":1238472228000},"page":"819-831","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":110,"title":["Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-\u03b2 and STAT3 activation"],"prefix":"10.1084","volume":"206","author":[{"given":"Atsushi","family":"Hosui","sequence":"first","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 1"},{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Kimura","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Yamaji","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-mei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risu","family":"Na","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar","family":"Hennighausen","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,3,30]]},"reference":[{"key":"2023072916394986900_bib1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/ng0501-29","article-title":"SOCS-1, a negative regulator of the JAK\/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity","volume":"28","author":"Yoshikawa","year":"2001","journal-title":"Nat. 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