Antiapoptotic effect of EGF on mouse hepatocytes associated with downregulation of proapoptotic Bid protein

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 285; no. 2; pp. G298 - G308
• Main Authors: Ethier, Chantal, Raymond, Valérie-Ann, Musallam, Lina, Houle, Robert, Bilodeau, Marc
• Format: Journal Article
• Language: English
• Published: United States 01.08.2003
• Subjects: Animals; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein; Blotting, Western; Carrier Proteins - genetics; Chromones - pharmacology; Enzyme Inhibitors - pharmacology; Epidermal Growth Factor - pharmacology; Gene Expression Regulation; Hepatocytes - cytology; Hepatocytes - drug effects; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Morpholines - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Polymerase Chain Reaction; Protein-Tyrosine Kinases - antagonists & inhibitors
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00040.2003

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.