Role of EGF receptor tyrosine kinase activity in antiapoptotic effect of EGF on mouse hepatocytes.
The apoptotic Fas pathway is potentially involved in the pathogenesis of liver diseases. Growth factors, such as epidermal growth factor (EGF), can protect cells against apoptosis induced by a variety of stimuli, including Fas receptor stimulation. However, the underlying mechanisms of this protection have yet to be determined. We investigated the involvement of EGF receptor (EGFR) tyrosine kinase (TK) activity in the antiapoptotic effect of EGF on primary mouse hepatocyte cultures. Cells undergoing apoptosis after treatment with anti-Fas antibody were protected by EGF treatment. This protection was significantly but partially decreased when cells were treated with two specific inhibitors of the TK activity of EGFR. Evaluation of the efficacy of these compounds indicated that they were able to abolish EGFR autophosphorylation and postreceptor events such as activation of mitogen-activated protein kinases and the phosphatidylinositol 3'-kinase pathways as well as increases in Bcl-x(L) mRNA and protein levels. This leads us to postulate that EGF exerts its antiapoptotic action partially through the TK activity of EGFR. In addition, our results suggest that Bcl-x(L) protein upregulation caused by EGF is linked to the TK activity of its receptor.
Musallam
L
L
Centre de Recherche, Centre Hospitalier de l'Université de Montréal-Hôpital Saint-Luc, Montreal, Quebec, Canada H2X 1P1.
Ethier
C
C
Haddad
P S
PS
Bilodeau
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002384:Catalysis / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein; D019014:fas Receptor / Q000187:drug effects / Q000502:physiology
C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D019014:fas Receptor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases