Transgenic expression in the liver of truncated Met blocks apoptosis and permits immortalization of hepatocytes

• Published in: The EMBO journal Vol. 16; no. 3; pp. 495 - 503
• Main Authors: Amicone, Laura, Spagnoli, Francesca M., Späth, Gerald, Giordano, Silvia, Tommasini, Cristina, Bernardini, Silvia, De Luca, Veronica, Rocca, Carlo Della, Weiss, Mary C., Comoglio, Paolo M., Tripodi, Marco
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.02.1997
• Subjects: alpha 1-Antitrypsin - genetics; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Apoptosis - genetics; Apoptosis - physiology; apoptosis protection; Blotting, Northern; Blotting, Southern; Blotting, Western; Cell Differentiation - genetics; cell polarity; Cells, Cultured; Gene Expression Regulation, Developmental - genetics; Hepatocyte Growth Factor - metabolism; Histocytochemistry; Humans; immortalized hepatocytes; Immunohistochemistry; Liver - metabolism; Met; Mice; Mice, Transgenic; Microscopy, Electron; Proto-Oncogenes - genetics; Receptor Protein-Tyrosine Kinases - genetics; Transgenes - genetics
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/16.3.495

Hepatocyte growth factor induces proliferation, motility and differentiation of epithelial cells through the tyrosine kinase receptor encoded by the MET proto‐oncogene. The cytoplasmic portion of Met (referred to as cyto‐Met) is activated but only weakly transforming. In order to determine the effect of activated Met on hepatocytes, we have targeted truncated Met expression to the liver by incorporating the cDNA into a vector carrying the entire human a‐1‐antitrypsin transcriptional unit. Transgenic expression in the liver of truncated human Met, containing the regulatory and the catalytic cytoplasmic domains, renders hepatocytes constitutively resistant to apoptosis and reproducibly permits immortalization. The emerging stable cell lines are not transformed and maintain a highly differentiated phenotype judged by the retention of epithelial cell polarity and the expression of hepatocyte‐enriched transcription factors as well as hepatic products.