{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:51:40Z","timestamp":1787989900529,"version":"build-2784847793"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T00:00:00Z","timestamp":1546214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T00:00:00Z","timestamp":1546214400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>TCPOBOP (1,4\u2010Bis [2\u2010(3,5\u2010Dichloropyridyloxy)] benzene) is a constitutive androstane receptor (CAR) agonist that induces robust hepatocyte proliferation and hepatomegaly without any liver injury or tissue loss. TCPOBOP\u2010induced direct hyperplasia has been considered to be CAR\u2010dependent with no evidence of involvement of cytokines or growth factor signaling. Receptor tyrosine kinases (RTKs), MET and epidermal growth factor receptor (EGFR), are known to play a critical role in liver regeneration after partial hepatectomy, but their role in TCPOBOP\u2010induced direct hyperplasia, not yet explored, is investigated in the current study. Disruption of the RTK\u2010mediated signaling was achieved using MET knockout (KO) mice along with Canertinib treatment for EGFR inhibition. Combined elimination of MET and EGFR signaling [MET KO + EGFR inhibitor (EGFRi)], but not individual disruption, dramatically reduced TCPOBOP\u2010induced hepatomegaly and hepatocyte proliferation. TCPOBOP\u2010driven CAR activation was not altered in [MET KO + EGFRi] mice, as measured by nuclear CAR translocation and analysis of typical CAR target genes. However, TCPOBOP\u2010induced cell cycle activation was impaired in [MET KO + EGFRi] mice due to defective induction of cyclins, which regulate cell cycle initiation and progression. TCPOBOP\u2010driven induction of FOXM1, a key transcriptional regulator of cell cycle progression during TCPOBOP\u2010mediated hepatocyte proliferation, was greatly attenuated in [MET KO + EGFRi] mice. Interestingly, TCPOBOP treatment caused transient decline in hepatocyte nuclear factor 4 alpha expression concomitant to proliferative response; this was not seen in [MET KO + EGFRi] mice. Transcriptomic profiling revealed the vast majority (~40%) of TCPOBOP\u2010dependent genes primarily related to proliferative response, but not to drug metabolism, were differentially expressed in [MET KO + EGFRi] mice. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP\u2010induced proliferative response without altering CAR activation.<\/jats:p>","DOI":"10.1002\/hep.30109","type":"journal-article","created":{"date-parts":[[2018,6,11]],"date-time":"2018-06-11T09:26:42Z","timestamp":1528709202000},"page":"1702-1718","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":49,"title":["TCPOBOP\u2010Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling"],"prefix":"10.1097","volume":"69","author":[{"given":"Bharat","family":"Bhushan","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine,University of Pittsburgh,Pittsburgh,Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Stoops","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine,University of Pittsburgh,Pittsburgh,Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy M.","family":"Mars","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine,University of Pittsburgh,Pittsburgh,Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Orr","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine,University of Pittsburgh,Pittsburgh,Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William 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