Dynamical effects of epigenetic silencing of 14-3-3sigma expression.

The development and progression of malignant tumours are often due to deregulated cell cycle control involving a plethora of different molecules. Among these, tumour suppressor proteins like p53 play a crucial role. p53 induces 14-3-3sigma, a multifunctional protein kinase inhibitor, centrally involved in cell cycle control and DNA damage repair after genotoxic stress. Recently, it has been shown that 14-3-3sigma is epigenetically silenced in a variety of tumours, which might contribute to tumour development and progression via impaired cell cycle control. In addition, p53, its inhibitor MDM2 and 14-3-3sigma form a signalling module in which 14-3-3sigma positively regulates the activity of p53 through feedback regulation. Here we present a mathematical model integrating the effects of 14-3-3sigma gene silencing, the dynamics of 14-3-3sigma induction and compartmentalisation by genotoxic stress and the role of interacting molecules p53 and MDM2. In vitro experiments with different melanoma cell lines were performed and our mathematical model was subjected to computer simulations to analyse different scenarios of activation depending on gene methylation status and DNA damage levels. Our analysis indicates that 14-3-3sigma expression is silenced by high gene methylation, but also that strong stimulation is necessary to induce 14-3-3sigma expression in cases of intermediate levels of gene methylation. More intriguingly, the model suggests that epigenetic silencing of 14-3-3sigma affects p53 dynamics in a synergistic way, such that the accumulative effect of partial downregulation of p53 expression and reduction of its nuclear fraction could affect drastically the activity of p53 as a transcription factor.