THE EPITHELIAL-CELL DEFAULT-PHENOTYPE HYPOTHESIS AND ITS IMPLICATIONSFOR CANCER

The expression of epithelial cell adhesion and cytoskeletal genes is o rchestrated by an apparently unique set of rules. No tissue-specific t ransactivator proteins have been found to drive them; only ubiquitous factors are utilized. In nonepithelial cells, they are actively repres sed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non-epithelial genes while inducing epith elial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the epithelial cell gene expression program is a transcriptional 'default'; that is, it occurs in the absence of tissue-specific transactivation. Conversion to tt-ii s default requires only that mesenchymal transactivators are not expre ssed, or that central 'integrator' proteins are inactive. In their abs ence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. On cogenes generally cause the breakdown of the epithelial phenotype - ge nerating carcinomas - so genes such as Ela that cause epithelial conve rsion may prove useful for both understanding and controlling cancer.