Molecular mechanisms in epithelial tumorigenesis : crosstalk between signaling pathways

The goal of this thesis was to identify novel regulators of epithelial cell transformation. We focused on two signaling pathways : the β-catenin pathway and the p53 pathway. β-catenin is a dual function protein that serves as both a structural cell skeleton component and a nuclear transcription factor. In more than 90% of colorectal cancers, β-catenin accumulates to inadequately high levels and activates transcription of target genes. The first part of the thesis focuses on the transcriptional program downstream of β-catenin. Based on microarray-based gene expression profiling in rat epithelial kidney cells, we have identified the insulin receptor substrate 1 (IRS1) as a direct transcriptional target gene of β-catenin, and provide evidence that cross-talk between β-catenin and insulin signaling is required for efficient initiation of cellular transformation. These findings will be discussed together with previous observations concerning a gene downregulated upon transformation by β-catenin (DRO1). p53 is a transcription factor that acts in the center of a tumor suppressive signaling network that coordinates the cellular response to different cellular stresses. Numerous protein-coding direct p53 target genes have been previously described that taken together lead to cell cycle arrest and/or programmed cell death. We have found the miRNA 34 family to be directly regulated by p53 and thoroughly characterized the mechanism of its transcriptional activation. Using both genetic inactivation and inducible overexpression models, we provided evidence that miRNA34 can downregulate the translation of the anti-apoptotic protein Bcl2 – thereby reinforcing the proapoptotic function of the protein-coding p53 target genes BAX and PUMA. We furthermore demonstrate that the majority of lung adenocarcinomas shows almost complete loss of miRNA34b and miRNA34c expression. Taken together, our data suggest that miRNA34s should be considered as novel tumor suppressor candidate genes.(SBIM 3) -- UCL, 200