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Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway.
Hepatology 2000; 32(3):528-35Hep

Abstract

Transforming growth factor beta (TGF-beta)-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-beta-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-beta disrupts the mitochondrial transmembrane potential (DeltaPsi(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-beta 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-beta. PI 3-kinase inhibitors completely block the protective effect of EGF on TGF-beta-induced bcl-x(L)down-regulation. We conclude that PI 3-kinase mediates the survival effect of EGF on TGF-beta-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.

Authors+Show Affiliations

Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia (Centro Mixto CSIC/UCM), Universidad Complutense de Madrid, Spain. isabelf@eucmax.sim.ucm.esNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10960445

Citation

Fabregat, I, et al. "Epidermal Growth Factor Impairs the Cytochrome C/caspase-3 Apoptotic Pathway Induced By Transforming Growth Factor Beta in Rat Fetal Hepatocytes Via a Phosphoinositide 3-kinase-dependent Pathway." Hepatology (Baltimore, Md.), vol. 32, no. 3, 2000, pp. 528-35.
Fabregat I, Herrera B, Fernández M, et al. Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. Hepatology. 2000;32(3):528-35.
Fabregat, I., Herrera, B., Fernández, M., Alvarez, A. M., Sánchez, A., Roncero, C., ... Benito, M. (2000). Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. Hepatology (Baltimore, Md.), 32(3), pp. 528-35.
Fabregat I, et al. Epidermal Growth Factor Impairs the Cytochrome C/caspase-3 Apoptotic Pathway Induced By Transforming Growth Factor Beta in Rat Fetal Hepatocytes Via a Phosphoinositide 3-kinase-dependent Pathway. Hepatology. 2000;32(3):528-35. PubMed PMID: 10960445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. AU - Fabregat,I, AU - Herrera,B, AU - Fernández,M, AU - Alvarez,A M, AU - Sánchez,A, AU - Roncero,C, AU - Ventura,J J, AU - Valverde,A M, AU - Benito,M, PY - 2000/8/29/pubmed PY - 2000/9/19/medline PY - 2000/8/29/entrez SP - 528 EP - 35 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 32 IS - 3 N2 - Transforming growth factor beta (TGF-beta)-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-beta-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-beta disrupts the mitochondrial transmembrane potential (DeltaPsi(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-beta 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-beta. PI 3-kinase inhibitors completely block the protective effect of EGF on TGF-beta-induced bcl-x(L)down-regulation. We conclude that PI 3-kinase mediates the survival effect of EGF on TGF-beta-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. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/10960445/Epidermal_growth_factor_impairs_the_cytochrome_C/caspase_3_apoptotic_pathway_induced_by_transforming_growth_factor_beta_in_rat_fetal_hepatocytes_via_a_phosphoinositide_3_kinase_dependent_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913900721860 DB - PRIME DP - Unbound Medicine ER -