Introduction of a Ha-ras oncogene into rat liver epithelial cells and parenchymal hepatocytes confers resistance to the growth inhibitory effects of TGF-beta.
Growth of rat liver epithelial cells (RLEC) and primary cultures of parenchymal hepatocytes is potently inhibited by TGF-beta. Transfection of a mutated Ha-ras oncogene, but not a human c-myc oncogene, into RLEC resulted in cell lines resistant to growth inhibition by TGF-beta under anchorage-dependent conditions. Infection of primary rat hepatocyte cultures with v-Ha-ras yielded a cell line likewise insensitive to inhibition by TGF-beta. Binding of [125I]TGF-beta to Ha-ras-transfected RLEC was reduced relative to control or c-myc-transfected cells. These data suggest that activation of a Ha-ras oncogene in epithelial cells may result in escape from negative growth control and hence be a critical step during carcinogenesis. However, although Ha-ras induced resistance to growth inhibition by TGF-beta under anchorage-dependent conditions, TGF-beta inhibited the spontaneous growth in soft agar of all cell lines containing the Ha-ras oncogene. This may reflect an alteration in regulation of extracellular matrix proteins and related enzymes responsible for anchorage-independent growth.
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.
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Michalopoulos
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D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells; D004848:Epithelium / Q000648:ultrastructure; D006801:Humans; D008099:Liver / Q000166:cytology / Q000648:ultrastructure; D015689:Oncogene Protein p21(ras); D009856:Oncogene Proteins, Viral / Q000378:metabolism; D009857:Oncogenes; D051381:Rats; D014162:Transfection; D015291:Transforming Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D009856:Oncogene Proteins, Viral; D015291:Transforming Growth Factors; D004247:DNA; D015689:Oncogene Protein p21(ras)