{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:56:59Z","timestamp":1791309419068,"version":"4.3.1"},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":6574,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,9]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>The human insulin receptor substrate-1 (hIRS-1) is a key intracellular protein involved in various cytokine signaling pathways associated with cell growth. We have previously demonstrated that stable transfection and overexpression of hIRS-1 in human hepatoblastoma cells <jats:italic toggle=\"yes\">in vitro<\/jats:italic> leads to the constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. In this setting, hIRS-1 acts as a dominant oncogene and will induce neoplastic transformation of NIH 3T3 cells. In the present study, the biologic effects of hIRS-1 overexpression in the liver was analyzed using both clinical tumor samples and a newly developed transgenic mouse model. We have found that approximately 40% of 22 human hepatocellular carcinoma (HCC) tumors had enhanced (&gt;200%) hIRS-1 gene expression compared with adjacent non-involved liver tissue. There was a significant relationship between the level of hIRS-1 overexpression and the tumor size; this finding suggests a possible role for hIRS-1 in tumor progression. To determine if downstream signal transduction cascades were activated by overexpression of hIRS-1 in hepatocytes, we established a transgenic mouse model using an hIRS-1 construct driven by an albumin promoter\/enhancer element to direct liver specific expression. The overexpressed hIRS-1 protein was found to be tyrosyl phosphorylated and interacted with downstream SH2-containing molecules such as the p85 subunit of phosphatidylinositol-3 kinase (PI3K), Grb2 adaptor, and SHP2 phosphatase proteins. The functional consequences of hIRS-1 overexpression were reflected by constitutive activation of both the MAPK and PI3K signal transduction cascades. More important, overexpression of hIRS-1 in the transgenic liver led to increased hepatocyte DNA synthesis. Our findings indicate that hIRS-1 overexpression induces downstream signaling molecules associated with hepatocyte growth and may potentially enhance tumor progression of HCC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.510260310","type":"journal-article","created":{"date-parts":[[2004,7,27]],"date-time":"2004-07-27T23:17:16Z","timestamp":1090970236000},"page":"598-604","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":93,"title":["Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes"],"prefix":"10.1097","volume":"26","author":[{"given":"S","family":"Tanaka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Mohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E V","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Sugimachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J R","family":"Wands","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.510260310","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-199709000-00011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T17:19:20Z","timestamp":1742836760000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-199709000-00011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,9]]},"references-count":0,"journal-issue":{"issue":"3","published-print":{"date-parts":[[1997]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.510260310","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[1997,9]]}}}