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

Abstract

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.

The Rac Exchange Factor Tiam1 Is Required for the Establishment and Maintenance of Cadherin-based Adhesions

“…The capacity of E1A to induce MET maps to its C terminus, encoded by exon 2 of the 12 S isoform (29). To date, the Cterminal binding protein is the only cellular factor identified that binds the C terminus of E1A (30,31).…”

“…In reporter assays and during fly and mouse development, the C terminus-binding protein functions as a transcriptional co-repressor (32)(33)(34). Indeed, the C-terminal binding protein is a strong candidate for an activity capable of co-repressing epithelial genes that is sequestered and inactivated by E1A (29,35). Thus far, the region of E1A responsible for inducing Tiam1 expression is unknown.…”

Changes in C-terminal Binding Protein 2 (CtBP2) Corepressor Complex Induced by E1A and Modulation of E1A Transcriptional Activity by CtBP2

“…However, CR4 exerts a strong negative regulatory effect on cooperative transformation with the activated Ras oncogene in primary epithelial cells (24,25,29,30). Cells transformed by Ras and E1A CR4 mutants are highly tumorigenic and invasive (24,29,31). Several CR4 mutants that cooperate with Ras more efficiently are deficient in interaction with CtBP (24,25) suggesting a link between recruitment of CtBP and retardation of the oncogene cooperating activity of E1A.…”

Change in gene expression subsequent to induction of Pnn/DRS/memA: increase in p21cip1/waf1

“…Adenovirus EIA oncoprotein, which is known to inhibit CBP, repressed b-catenin-dependent transcriptional activation (Takemaru and Moon, 2000). Intriguingly, EIA, like Pnn, has been shown to positively impact epitheliogenesis by transcriptionally inducing an array of epithelial cell adhesion genes while repressing other genes, thus producing an epithelial phenotype (Frisch, 1994(Frisch, , 1997Fischer and Quinlan, 1998). While EIA protein can interact with nuclear acetylases, p300, CBP, P/CAF and co-repressor CtBP (Fischer and Quinlan, 1998;Jones, 1995), it seems that EIA-CtBP interaction accounts for the activation of epithelial cell adhesion genes (Frisch, 1997;Grooteclaes and Frisch, 2000).…”

“…Intriguingly, EIA, like Pnn, has been shown to positively impact epitheliogenesis by transcriptionally inducing an array of epithelial cell adhesion genes while repressing other genes, thus producing an epithelial phenotype (Frisch, 1994(Frisch, , 1997Fischer and Quinlan, 1998). While EIA protein can interact with nuclear acetylases, p300, CBP, P/CAF and co-repressor CtBP (Fischer and Quinlan, 1998;Jones, 1995), it seems that EIA-CtBP interaction accounts for the activation of epithelial cell adhesion genes (Frisch, 1997;Grooteclaes and Frisch, 2000). Interestingly, Snail, a transcription factor, which represses the transcription of E-cadherin and drives epithelial to mesenchymal transformation, may also mediate its repression through interactions with CtBP or other similar co-repressors (Batlle et al, 2000;Cano et al, 2000;Criqui-Filipe et al, 1999;Nibu et al, 1998).…”