RESISTANCE TO TGF-BETA IN SV40 LARGE T-IMMORTALIZED RAT INTESTINAL EPITHELIAL-CELLS IS ASSOCIATED WITH DOWN-REGULATION OF TGF-BETA TYPE-I RECEPTOR

A new continuous cell line designated ESKI-1 was established by transf ection of rat fetal intestinal epithelial cells with ecotropic retrovi ruses containing SV40 large T oncogene. The ESKI-1 cell line exhibits morphologic features of an epithelial cell line and expresses the OCI- 5 and cytokeratin 8 transcripts associated with epithelial cells in th e small intestine. Signal transduction and proliferation responses to TGF beta has been characterized in ESKI-1 cells, in comparison with th e spontaneously-immortalized IEC cell lines originating from neonatal rat duodenum and ileum. ESKI-1 express both TGF alpha and TGF beta. Ho wever, despite a marked increase in TGF beta-stimulated p78 kinase act ivity observed in ESKI-1 and IEC cells, TGF beta did not modulate grow th, or extracellular matrix expression in ESKI-1 cells. Resistance to growth modulation was associated with downregulation of TGF beta. Type I receptor expression in the SV40 large T-immortalized cells. Thus, p roliferative resistance to TGF beta inhibition can result from depleti on of the TGF beta type I receptor and disruption of the TGF beta sign aling pathway downstream the p78 serine/threonine kinase. These molecu lar defects constitute two early events during the SV40LT-mediated imm ortalization and neoplastic progression of the intestinal epithelia.