Antiapoptotic effect of EGF on mouse hepatocytes associated with downregulation of proapoptotic Bid protein.
Growth factors have been shown to protect cells from a variety of apoptotic stimuli. In the liver, the Fas system is thought to be very important in the genesis of hepatocyte apoptosis. Others have already shown the importance of the phosphatidylinositol 3-kinase (PI3-kinase) pathway and of increased Bcl-xl expression in the antiapoptotic effect of growth factors on hepatocytes. We investigated the effect of EGF on Bid, a BH3-only member of the Bcl-2 family and a major player in the transduction of the Fas apoptotic signal. Hepatocyte apoptosis was induced in vitro with a purified anti-mouse Fas antibody. The effect of EGF on Bid protein expression was studied on those cultures. EGF dose dependently reduced the expression of Bid protein in primary mouse hepatocyte cultures independently of Fas stimulation. This decrease was not the result of the degradation of Bid into its active p15 fragment. Treating cells with a specific inhibitor of the EGF receptor autophosphorylation completely abolished the decrease in Bid expression afforded by EGF. Treatment with LY-294002, a PI3-kinase blocker, partly reverted the effect of EGF. When apoptosis was induced in Bid-deficient hepatocytes, EGF lost its capacity to protect cells against this type of cell death. These results show that EGF decreases the expression of Bid protein and suggest that the effect of EGF on Bid is one of the mechanisms of the antiapoptotic effect of EGF.
Ethier
Chantal
C
Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre Hospitalier de l' Université de Montréal-Hôpital Saint-Luc, Montreal, Quebec, Canada.
Raymond
Valérie-Ann
VA
Musallam
Lina
L
Houle
Robert
R
Bilodeau
Marc
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C494815:Bid protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one