title: Prostaglandin E2 receptor EP4 agonist induces Bcl-xL and independently activates proliferation signals in mouse primary hepatocytes.
abstract: BACKGROUND
  To improve the survival rate of fulminant hepatic failure (FHF), we examined the mechanism of the antiapoptotic effect, and the possible proliferative effect, of a specific agonist of prostaglandin E2 receptor EP4 (PGEP4-A) on mouse primary hepatocytes, as a candidate for a new therapeutic agent.
  
  
  METHODS
  The expression of four PGE2 receptor subtypes was detected by a reverse transcriptase polymerase chain reaction (PCR) method. Hepatocytes were stimulated with PGEP4-A, ONO-AE1-437, and changes in the expression levels of Bcl-xL and cyclin D1 and in the phosphorylation of epidermal growth factor receptor (EGF-R) and extracellular-signal related kinase (ERK) were examined by Western blot analysis.
  
  
  RESULTS
  Mouse primary hepatocytes constitutively expressed the mRNAs of all four PGE2 receptor subtypes, including that of PGEP4. PGEP4-A induced not only Bcl-xL protein expression (as we had previously demonstrated in HepG2 cells) but also induced cyclin D1 protein expression in mouse primary hepatocytes as well as the phosphorylation of EGF-R and ERK. The inhibition of ERK phosphorylation by a specific inhibitor, PD98059, did not affect the increase in Bcl-xL expression level.
  
  
  CONCLUSIONS
  PGEP4-A may be a therapeutic agent for FHF because of its antiapoptotic and regenerative effects on hepatocytes.
authors: First Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors: Kojiro
authors: K
authors: Kataoka
authors: Yasuhiro
authors: Y
authors: Takikawa
authors: Shi De
authors: SD
authors: Lin
authors: Kazuyuki
authors: K
authors: Suzuki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D056741:Cyclin D; D016213:Cyclins; D005419:Flavonoids; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D051020:bcl-X Protein; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one