title: Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation.
abstract: Regulation of liver cell proliferation is a key event to control organ size during development and liver regeneration. Methionine adenosyltransferase (MAT) 2A is expressed in proliferating liver, whereas MAT1A is the form expressed in adult quiescent hepatocytes. Here we show that, in H35 hepatoma cells, growth factors such as hepatocyte growth factor (HGF) and insulin up-regulated MAT2A expression. HGF actions were time- and dose-response dependent and required transcriptional activity. Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-phosphate kinase (PI 3-K) pathways were required for both HGF-induced cell proliferation and MAT2A up-regulation. Furthermore, in H35 cells treated with HGF, the inhibition of these pathways was associated with the switch from the expression of fetal liver MAT2A to the adult liver MAT1A isoform. Fetal liver hepatocytes exhibited an identical response pattern. Treatment of H35 hepatoma cells with MAT2A antisense oligonucleotides decreased cell proliferation induced by HGF; this decrease correlated with the decay in MAT2A messenger RNA (mRNA) levels. Finally, growth inhibitors such as transforming growth factor (TGF) beta blocked HGF-induced MAT2A up-regulation while increasing MAT1A mRNA levels in H35 cells. In conclusion, our results show that MAT2A expression not only correlates with liver cell proliferation but is required for this process.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. cpaneda@iib.uam.es
authors.forename: Covadonga
authors.initials: C
authors.lastname: Pañeda
authors.forename: Itziar
authors.initials: I
authors.lastname: Gorospe
authors.forename: Blanca
authors.initials: B
authors.lastname: Herrera
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Isabel
authors.initials: I
authors.lastname: Fabregat
authors.forename: Isabel
authors.initials: I
authors.lastname: Varela-Nieto
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular; D002455:Cell Division / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000201:enzymology*; D008113:Liver Neoplasms; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D008716:Methionine Adenosyltransferase