Abstract
Transforming growth factor beta1 (TGF-beta1) belongs to a family of polypeptide factors, whose cytostatic and apoptotic functions help restrain the growth of mammalian cells. Although solid data established the role of TGF-beta's as suppressor factors in tumorigenic processes, in the context of an advanced stage of disease, TGF-beta's could also play a pro-oncogenic role. We have previously shown that TGF-beta1 induces both pro- and anti-apoptotic signals in foetal rat hepatocytes. In this work, we have focused on its anti-apoptotic mechanism. We show that TGF-beta1 activates the epidermal growth factor receptor (EGFR) and phosphorylates c-Src. EGFR is required for Akt activation. Blocking EGFR signalling amplifies the apoptotic response to TGF-beta1. TGF-beta1 induced a rapid activation of the tumour necrosis factor-alpha-converting enzyme (TACE/ADAM (a disintegrin and metalloprotease) 17). Inhibitors of TACE considerably attenuated Akt activation, which suggests that TGF-beta1 activates EGF signalling in hepatocytes by promoting shedding of EGF-like ligands. The activation of c-Src by TGF-beta1 is EGFR dependent and is required for full Akt phosphorylation and cell survival. Inhibition of EGFR does not block the epithelial-mesenchymal transition (EMT) induced by TGF-beta1 in hepatocytes, which indicates that activation of EGFR plays an essential role in impairing apoptosis, but it is dispensable for the EMT process.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Caspase 3
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Caspases / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Class Ib Phosphatidylinositol 3-Kinase
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Epithelial Cells / metabolism
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ErbB Receptors / metabolism*
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Hepatocytes / cytology*
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Hepatocytes / drug effects
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Hepatocytes / metabolism*
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Isoenzymes / metabolism
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Liver / cytology
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Liver / embryology
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Mesoderm / metabolism
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Metalloendopeptidases / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins pp60(c-src) / drug effects
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Proto-Oncogene Proteins pp60(c-src) / metabolism*
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Rats
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Rats, Wistar
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Signal Transduction
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Isoenzymes
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Proto-Oncogene Proteins
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Tgfb1 protein, rat
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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Class Ib Phosphatidylinositol 3-Kinase
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Pik3cg protein, rat
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ErbB Receptors
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Proto-Oncogene Proteins pp60(c-src)
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Casp3 protein, rat
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Caspase 3
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Caspases
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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Adam17 protein, rat