The C Terminus of E1A Regulates Tumor Progression and Epithelial Cell Differentiation

• Published in: Virology (New York, N.Y.) Vol. 249; no. 2; pp. 427 - 439
• Main Authors: Fischer, Robert S., Quinlan, Margaret P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.09.1998
• Subjects: actin; Actins - metabolism; Adenovirus; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - physiology; Adenoviruses, Human - genetics; Adenoviruses, Human - pathogenicity; Animals; Cell Differentiation - genetics; Cell Transformation, Neoplastic; Cell Transformation, Viral; cell-cell junctional complexes; Cells, Cultured; cytoskeleton; EMT; Epithelial Cells - cytology; Genes, Tumor Suppressor; Genes, Viral; Humans; Membrane Proteins - genetics; Membrane Proteins - physiology; MET; Mutation; Oncogenes; Phosphoproteins - genetics; Phosphoproteins - physiology; Rats; Tight Junctions - genetics; Tight Junctions - physiology; Transfection; Zonula Occludens-1 Protein; actin; cell-cell junctional complexes; cytoskeleton; EMT; MET
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1006/viro.1998.9337

The E1A gene of adenovirus has been considered both a dominant oncogene and a tumor suppressor. It has been reported to induce epithelial cell but to prevent myoblast differentiation. E1A enables oncogenes that are unable to transform primary cells on their own to do so, yet suppresses tumor progression toward invasion and metastasis. To try to reconcile the seemingly, conflicting E1A phenotypes, we examined the expression of epithelial cell specific and characterizing proteins in immortalized or tumorigenically transformed primary epithelial cells expressing wild-type E1A or a C-terminal mutant that has lost tumor suppressive abilities. All the cell types continued to express cytokeratin. Epithelial cell morphology, social behavior, and growth characteristics were retained by cells expressing wild-type E1A, even in the presence of an activated ras oncogene. Mutant E1A-expressing cells were less well differentiated even in the absence of ras. They were specifically defective in cell–cell junctional complexes, such as tight and adherens junctions and desmosomes. There was also a preference for those actin structures prominent in fibroblasts: stress fibers and filopodia, while in the wild-type E1A expressing cells, cortical actin and circumferential actin filaments were dominant. Thus the E1A-mutant-expressing cells were already predisposed to a more advanced tumor stage even when they were only immortalized and not transformed. The results suggest the possibility that the C terminus of E1A may be involved in regulating epithelial mesenchymal transitions, which have previously been linked to tumor progression.