Mechanism of growth promoting activity of epiregulin in primary cultures of rat hepatocytes.
In spite of lower receptor affinity, epiregulin exhibits a stronger stimulation of DNA synthesis than epidermal growth factor (EGF) in rat hepatocytes. To determine the mechanism of stimulation, we examined the activities of epiregulin on growth stimulation, signal transduction, and mRNA induction of hepatotrophic factors in primary cultures of rat hepatocytes. Epiregulin stimulated hepatocyte proliferation as efficiently as hepatotrophic factors, including heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-alpha). Epiregulin induced a more prolonged activation of EGF receptor (EGFR) and p42/44 mitogen-activated protein kinase (MAPK) than EGF. Furthermore, epiregulin up-regulated the mRNAs of TGF-alpha and HB-EGF, and in turn, these growth factors enhanced the expression of epiregulin mRNA. In vivo, increased production of epiregulin was noted in extracts of the remnant liver obtained 24 h after partial hepatectomy, and EGFR phosphorylation by these extracts was partially inhibited by anti-epiregulin antibody. Our results showed a more potent hepatocyte proliferative activity for epiregulin compared with EGF in vitro, which depends on prolonged activation of EGFR and p42/44 MAPK. Our findings suggest that epiregulin may play significant roles in liver regeneration following partial hepatectomy in cooperation with other growth factors.
Komurasaki
Toshi
T
Department of Molecular and Cellular Biology, Molecular Biology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. toshi.komurasaki@po.rd.taisho.co.jp
Toyoda
Hitoshi
H
Uchida
Daisuke
D
Nemoto
Nobuo
N
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066260:Epiregulin; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D015854:Up-Regulation
C587880:EREG protein, human; D066260:Epiregulin; C587882:Ereg protein, rat; D008024:Ligands; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases