The master regulators Myc and p53 cellular signaling and functions in polycystic kidney disease

The transcription factors Myc and p53 associated with oncogenesis play determinant roles in a human genetic disorder, autosomal dominant polycystic kidney disease (ADPKD), that was coined early in ADPKD etiology a «neoplasia in disguise ». These factors are interdependent master cell regulators of major biological processes including proliferation, apoptosis, cell growth, metabolism, inflammation, fibrosis and differentiation that are all modulated in ADPKD. Myc and p53 proteins evolved to respond and carry out overlapping functions via opposing mechanisms of action. Studies in human ADPKD kidneys, caused by mutations in the PKD1 or PKD2 genes, reveal reduced p53 expression and high expression of Myc in the cystic tubular epithelium. Myc and p53 via direct interaction act respectively, as transcriptional activator and repressor of PKD1 gene expression, consistent with increased renal PKD1 levels in ADPKD. Mouse models generated by Pkd1 and Pkd2 gene dosage dysregulation reproduce renal cystogenesis with activation of Myc expression and numerous signaling pathways, strikingly similar to those determined in human ADPKD. In fact, upregulation of renal Myc expression is also detected in virtually all non-orthologous animal models of PKD. A definitive causal connection of Myc with cystogenesis was established by renal overexpression of Myc in transgenic mice that phenocopies human ADPKD. The network of activated signaling pathways in human and mouse cystogenesis individually or in combination can target Myc as a central node of PKD pathogenesis. One or many of the multiple functions of Myc upon activation can play a role in every phases of ADPKD development and lend credence to the notion of "Myc addiction" for cystogenesis. We propose that the residual p53 levels are conducive to an ADPKD biological program without cancerogenesis while a "p53 dependent annihilation" mechanism would be permissive to oncogenesis. Of major importance, Myc ablation in orthologous mouse models or direct inhibition in non-orthologous mouse model significantly delays cystogenesis consistent with pharmacologic or genetic inhibition of Myc upstream regulator or downstream targets in the mouse. Together, these studies on PKD proteins upon dysregulation not only converged on Myc as a focal point but also attribute to Myc upregulation a causal and « driver » role in pathogenesis. This review will present and discuss our current knowledge on Myc and p53, focused on PKD mouse models and ADPKD.