Activation of NADPH oxidase by transforming growth factor-β in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-κB-dependent mechanism

The TGF-β (transforming growth factor-β) 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 α-converting enzyme)/ADAM17 (a...

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Veröffentlicht in:Biochemical journal 2007-07, Vol.405 (2), p.251-259
Hauptverfasser: Murillo, Miguel M., Carmona-Cuenca, Irene, del Castillo, Gaelle, Ortiz, Conrad, Roncero, César, Sánchez, Aránzazu, Fernández, Margarita, Fabregat, Isabel
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container_issue 2
container_start_page 251
container_title Biochemical journal
container_volume 405
creator Murillo, Miguel M.
Carmona-Cuenca, Irene
del Castillo, Gaelle
Ortiz, Conrad
Roncero, César
Sánchez, Aránzazu
Fernández, Margarita
Fabregat, Isabel
description The TGF-β (transforming growth factor-β) 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 α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17; one of the metalloproteases involved in shedding of the EGFR ligands) and up-regulation of TGF-α 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-β in foetal rat hepatocytes. The potential involvement of ROS (reactive oxygen species), an early signal induced by TGF-β, 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 TβR-I (TGF-β 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-β up-regulates nox4 and increases the levels of Rac1 protein, a known regulator of both Nox1 and Nox2, in a TβR-I-dependent manner. TGF-β mediates activation of the nuclear factor-κB pathway, which is inhibited by DPI and is required for up-regulation of TGF-α and HB-EGF. In contrast, EGFR activation is not required for TGF-β-induced up-regulation of those ligands. Considering previous work that has established the role of ROS in apoptosis induced by TGF-β in hepatocytes, the results of the present study indicate that ROS might mediate both pro- and anti-apoptotic signals in TGF-β-treated cells.
doi_str_mv 10.1042/BJ20061846
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Different members of the NOX family of genes are expressed in hepatocytes, included nox1, nox2 and nox4. TGF-β up-regulates nox4 and increases the levels of Rac1 protein, a known regulator of both Nox1 and Nox2, in a TβR-I-dependent manner. TGF-β mediates activation of the nuclear factor-κB pathway, which is inhibited by DPI and is required for up-regulation of TGF-α and HB-EGF. In contrast, EGFR activation is not required for TGF-β-induced up-regulation of those ligands. 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Different members of the NOX family of genes are expressed in hepatocytes, included nox1, nox2 and nox4. TGF-β up-regulates nox4 and increases the levels of Rac1 protein, a known regulator of both Nox1 and Nox2, in a TβR-I-dependent manner. TGF-β mediates activation of the nuclear factor-κB pathway, which is inhibited by DPI and is required for up-regulation of TGF-α and HB-EGF. In contrast, EGFR activation is not required for TGF-β-induced up-regulation of those ligands. 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title Activation of NADPH oxidase by transforming growth factor-β in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-κB-dependent mechanism
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