title: Transforming growth factor-beta activates both pro-apoptotic and survival signals in fetal rat hepatocytes.
abstract: Transforming growth factor-beta (TGF-beta) induces apoptosis in fetal rat hepatocytes. However, a subpopulation of these cells survives concomitant with changes in morphology and phenotype, reminiscent of an epithelial mesenchymal transition (EMT) [Exp. Cell Res. 252 (1999) 281-291]. In this work, we have isolated the subpopulation that survives to TGF-beta-induced apoptosis, showing that these cells maintain the response to TGF-beta in terms of Smads activation and growth inhibition. Analyses of the intracellular signals that could impair the apoptotic effects of TGF-beta have indicated that the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway is activated in these resistant cells. Experiments in fetal rat hepatocytes have shown that TGF-beta is able to transiently activate PI 3-K/Akt by a mechanism independent of protein synthesis but dependent on a tyrosine kinase activity. Pro-apoptotic signals, such as oxidative stress and caspases, contribute to the loss of Akt at later times. Inhibiting PI 3-K sensitizes fetal hepatocytes (FH) to the apoptosis induced by TGF-beta and causes spontaneous death in the resistant cells. In conclusion, TGF-beta, as it is known for other cytokines, could be inducing pro-apoptotic and survival signals in hepatocytes, the balance among them will decide cell fate.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Valdés
authors.forename: Miguel M
authors.initials: MM
authors.lastname: Murillo
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.forename: Blanca
authors.initials: B
authors.lastname: Herrera
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Sánchez
authors.forename: Manuel
authors.initials: M
authors.lastname: Benito
authors.forename: Margarita
authors.initials: M
authors.lastname: Fernández
authors.forename: Isabel
authors.initials: I
authors.lastname: Fabregat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D053148:Caspase 3; D020169:Caspases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C505407:CASP3 protein, human; C505410:Casp3 protein, rat