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Evidence for a function of CtBP in epithelial gene regulation and anoikis
1The Burnham Institute, La Jolla, California 92037, USA.
Abstract:
Previously, we reported that adenovirus E1a protein behaves as a tumor suppressor in human cells. It apparently functions by transcriptionally inducing an array of epithelial cell adhesion genes, while repressing other cell-type specific genes, thus producing an epithelial phenotype. Concomitantly, the cells become sensitive to anoikis (apoptosis of epithelial cells detached from extracellular matrix), potentially causing tumor suppression. E1a protein interacts with the nuclear acetylases p300, CBP and P/CAF, and also with the co-repressor protein CtBP. In this study, we have determined the role of these interactions in E1a's phenotypic effects on human tumor cells. The results indicate that E1a's interaction with CtBP activates at least three epithelial cell adhesion gene promoters. The E-cadherin repressor appeared to be the CtBP-interacting protein delta EF1/ZEB, which bound the ras-repressible E-boxes of the E-cadherin promoter. The E1a-CtBP interaction also contributed to anoikis-sensitization. E1a's interactions with the nuclear acetylases conferred epithelial morphologies but did not activate epithelial genes. These latter interactions did not sensitize tumor cells to anoikis but nevertheless conferred tumor suppression. These results implicate CtBP as an antagonist of the epithelial phenotype and anoikis. They also indicate a new but undefined role for nuclear acetylases in maintaining the transformed phenotype.
Insights
Adenovirus E1a protein suppresses tumors by inducing epithelial characteristics and anoikis sensitivity through interactions with CtBP. Nuclear acetylase interactions also suppress tumors but do not induce anoikis.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Adenovirus E1a protein previously reported as a tumor suppressor in human cells.
- E1a induces epithelial phenotype and anoikis sensitivity by regulating gene expression.
- E1a interacts with nuclear acetylases (p300, CBP, P/CAF) and co-repressor CtBP.
Purpose of the Study:
- To determine the role of E1a's interactions with p300, CBP, P/CAF, and CtBP in its phenotypic effects on human tumor cells.
- Investigate the mechanism by which E1a induces epithelial characteristics and anoikis sensitivity.
Main Methods:
- Studied interactions between E1a, CtBP, nuclear acetylases, and gene promoters in human tumor cells.
- Analyzed the role of delta EF1/ZEB in E-cadherin regulation.
- Assessed the impact of these interactions on epithelial phenotype and anoikis sensitivity.
Main Results:
- E1a-CtBP interaction activates epithelial cell adhesion gene promoters, including E-cadherin via repression of delta EF1/ZEB.
- E1a-CtBP interaction contributes to anoikis sensitization.
- E1a interactions with nuclear acetylases confer epithelial morphology and tumor suppression without activating epithelial genes or sensitizing to anoikis.
Conclusions:
- CtBP acts as an antagonist of the epithelial phenotype and anoikis.
- Nuclear acetylases play a role in maintaining the transformed phenotype, independent of epithelial gene activation or anoikis sensitization.
- E1a's tumor suppressor function is mediated through distinct interactions with CtBP and nuclear acetylases.