c-Myc Signalling in the genetic mechanism of polycystic kidney disease

Abstract

The Myc family of transcription factors regulates major biological processes such as proliferation, stem/progenitor cell pluripotency, metabolism, apoptosis, cell growth and differentiation. The most-studied member c-Myc is essential in embryonic development and cellular homeostasis. Dysregulation of c-Myc protein function is not only associated with malignant transformation and human tumors but is also implicated in autosomal dominant polycystic kidney disease (ADPKD), a human genetic disorder, considered a neoplasia in disguise. Studies from human ADPKD kidneys, caused by mutation in the PKD1 or PKD2 genes, revealed high expression of c-Myc with strong signal detected over cystic tubular epithelium. Consistent with human ADPKD pathogenesis, mouse models produced by dysregulation of Pkd1 and Pkd2 gene dosage show stimulation of renal c-Myc expression. Induced renal c-Myc expression is also observed in several non-orthologous animal models of PKD. Significantly, c-Myc overexpression specifically targeted to renal epithelial cells in transgenic mice closely reproduces human ADPKD. The specific causal effect of c-Myc in PKD was demonstrated by targeting different oncogenes which could not mimic the PKD phenotype. In fact, c-Myc was shown to be a major mediator of renal cystogenesis through various mechanisms and signalling pathways. Most importantly, inhibition of c-Myc in vivo, directly by repressing translation or indirectly with a small-molecule inhibitor, significantly delayed cystogenesis in the mouse. In summary, c-Myc is a central node in the pathogenesis of Pkd1/Pkd2 mouse models and of human ADPKD development and progression.