THE C-TERMINUS OF E1A REGULATES TUMOR PROGRESSION AND EPITHELIAL-CELLDIFFERENTIATION

The E1A gene of adenovirus has been considered both a dominant oncogen e and a tumor suppressor. It has been reported to induce epithelial ce ll but to prevent myoblast differentiation. E1A enables oncogenes that are unable to transform primary cells on their own to do so, yet supp resses tumor progression toward invasion and metastasis. To try to rec oncile the seemingly, conflicting E1A phenotypes, we examined the expr ession of epithelial cell specific and characterizing proteins in immo rtalized or tumorigenically transformed primary epithelial cells expre ssing wild-type EIA or a C-terminal mutant that has lost tumor suppres sive abilities. All the cell types continued to express cytokeratin. E pithelial cell morphology, social behavior, and growth characteristics were retained by cells expressing wild-type E1A, even in the presence of an activated res oncogene. Mutant E1A-expressing cells were less w ell differentiated even in the absence of ras. They were specifically defective in cell-cell junctional complexes, such as tight and adheren s junctions and desmosomes. There was also a preference for those acti n structures prominent in fibroblasts: stress fibers and filopodia, wh ile in the wild-type E1A expressing cells, cortical actin and circumfe rential actin filaments were dominant. Thus the E1A-mutant-expressing cells were already predisposed to a more advanced tumor stage even whe n they were only immortalized and not transformed. The results suggest the possibility that the C terminus of E1A may be involved in regulat ing epithelial mesenchymal transitions, which have previously been lin ked to tumor progression. (C) 1998 Academic Press.