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Epidermal Growth Factor Impairs the Cytochrome C/Caspase‐3 Apoptotic Pathway Induced by Transforming Growth Factor β in Rat Fetal Hepatocytes Via a Phosphoinositide 3‐Kinase–Dependent Pathway
Author(s) -
Fabregat Isabel,
Herrera Blanca,
Fernández Margarita,
Álvarez Alberto M.,
Sánchez Aránzazu,
Roncero César,
Ventura JuanJosé,
Valverde Ángela M.,
Benito Manuel
Publication year - 2000
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2000.9774
Subject(s) - epidermal growth factor , biology , microbiology and biotechnology , protein kinase b , mapk/erk pathway , phosphoinositide 3 kinase , kinase , signal transduction , protein kinase a , ask1 , mitogen activated protein kinase kinase , biochemistry , receptor
Transforming growth factor β (TGF‐β)–mediated apoptosis is one of the major death processes in the liver. We have previously shown that epidermal growth factor (EGF) is an important survival signal for TGF‐β–induced apoptosis in fetal hepatocytes (Fabregat et al., FEBS Lett 1996;384:14‐18). In this work we have studied the intracellular signaling implicated in the protective effect of EGF. We show here that EGF activates p42 and p44 mitogen‐activated protein kinases (MAPK). However, mitogen extracellular kinase (MEK) inhibitors do not block the survival effect of EGF. EGF also activates phosphoinositide 3‐kinase (PI 3‐kinase) and protein kinase B (PKB/AKT) in these cells. The presence of PI 3‐kinase inhibitors blocks the protective effect of EGF on cell viability, DNA fragmentation, and caspase‐3 activity. We have found that TGF‐β disrupts the mitochondrial transmembrane potential (Δψ m )and activates the release of cytochrome c, this effect being blocked by EGF, via a PI 3‐kinase–dependent pathway. A detailed study on bcl‐2 superfamily gene expression shows that TGF‐β produces a decrease in the messenger RNA (mRNA) and protein levels of bcl‐x L , an antiapoptotic member of this family, capable of preventing cytochrome c release. EGF is able to maintain bcl‐x L levels even in the presence of TGF‐β. PI 3‐kinase inhibitors completely block the protective effect of EGF on TGF‐β–induced bcl‐x L down‐regulation. We conclude that PI 3‐kinase mediates the survival effect of EGF on TGF‐β–induced death by acting upstream from the mitochondrial changes, i.e., preventing bcl‐x L down‐regulation, cytochrome c release, and activation of caspase‐3.