title: Activation of NADPH oxidase by transforming growth factor-beta in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-kappaB-dependent mechanism.
abstract: The TGF-beta (transforming growth factor-beta) induces survival signals in foetal rat hepatocytes through transactivation of EGFR (epidermal growth factor receptor). The molecular mechanism is not completely understood, but both activation of the TACE (tumour necrosis factor alpha-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17; one of the metalloproteases involved in shedding of the EGFR ligands) and up-regulation of TGF-alpha and HB-EGF (heparin-binding epidermal growth factor-like growth factor) appear to be involved. In the present study, we have analysed the molecular mechanisms that mediate up-regulation of the EGFR ligands by TGF-beta in foetal rat hepatocytes. The potential involvement of ROS (reactive oxygen species), an early signal induced by TGF-beta, and the existence of an amplification loop triggered by initial activation of the EGFR, have been studied. Results indicate that DPI (diphenyleneiodonium) and apocynin, two NOX (NADPH oxidase) inhibitors, and SB431542, an inhibitor of the TbetaR-I (TGF-beta receptor I), block up-regulation of EGFR ligands and Akt activation. Different members of the NOX family of genes are expressed in hepatocytes, included nox1, nox2 and nox4. TGF-beta up-regulates nox4 and increases the levels of Rac1 protein, a known regulator of both Nox1 and Nox2, in a TbetaR-I-dependent manner. TGF-beta mediates activation of the nuclear factor-kappaB pathway, which is inhibited by DPI and is required for up-regulation of TGF-alpha and HB-EGF. In contrast, EGFR activation is not required for TGF-beta-induced up-regulation of those ligands. Considering previous work that has established the role of ROS in apoptosis induced by TGF-beta in hepatocytes, the results of the present study indicate that ROS might mediate both pro- and anti-apoptotic signals in TGF-beta-treated cells.
authors.affiliation: Fundació Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Centre d'Oncologia Molecular, L'Hospitalet, Barcelona, Spain.
authors.forename: Miguel M
authors.initials: MM
authors.lastname: Murillo
authors.forename: Irene
authors.initials: I
authors.lastname: Carmona-Cuenca
authors.forename: Gaelle
authors.initials: G
authors.lastname: Del Castillo
authors.forename: Conrad
authors.initials: C
authors.lastname: Ortiz
authors.forename: César
authors.initials: C
authors.lastname: Roncero
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Sánchez
authors.forename: Margarita
authors.initials: M
authors.lastname: Fernández
authors.forename: Isabel
authors.initials: I
authors.lastname: Fabregat
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D009861:Onium Compounds / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines; D051381:Rats; D017382:Reactive Oxygen Species / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000098:Acetophenones; D000873:Anthracenes; D001549:Benzamides; D002867:Chromones; D004149:Dioxoles; D005419:Flavonoids; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D016328:NF-kappa B; D009861:Onium Compounds; D010455:Peptides; D011799:Quinazolines; D017382:Reactive Oxygen Species; C118258:SN50 peptide; D016212:Transforming Growth Factor beta; D020032:Tyrphostins; C101044:RTKI cpd; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004815:Epidermal Growth Factor; C007517:diphenyleneiodonium; C056165:acetovanillone; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614712:NOX1 protein, rat; C498911:Nox4 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one