Cell-cycle and cancer-associated gene networks activated by Dsg2: evidence of cystatin A deregulation and a potential role in cell. Mus musculus

Our recently generated transgenic mouse model in which Dsg2 is overexpressed in the epidermis observed notable epidermal hyperplasia. We described how Dsg2 altered a number of genes important in epithelial cell growth including the cysteine protease inhibitor cystatin A. We offer a novel pathway of cystatin A regulation involving Dsg2 and a potential crosstalk between Dsg2 and CSTA that modulates cell adhesion. Overall design: In this study, we used microarray and gene network analysis to compare full-thickness skin of Inv-Dsg2 transgenic mice overexpressing Dsg2 in the superficial layer of the skin compared to wild-type mouse skin expressing Dsg2 in the basal layer of the epidermis. We found 492 genes were altered by more than two-fold in response to Dsg2 that were important in epithelial dysplasia. We focused on the upregulation of Cystatin A, a cysteine protease inhibitor, that is deregulated and mutated in several skin cancers and skin fragility disorders. By knockdown of either Dsg2 or CSTA and by dual knockdown of Dsg2 and CSTA we show that there is increased susceptibility of cell-cell disadhesion and cytoplasmic localization of Dsg2 in response to mechanical stress.