Rheostat-like Regulation of the cytoplasmic C-terminal tail of Polycystin-1 in Polycystic Kidney Disease

Mutations in PKD1, the gene encoding the transmembrane protein Polycystin-1 (PC-1), account for 85 percent of Polycystic Kidney Disease cases. PC-1 is known to play a vital role in renal tubular development and kidney function. The cytoplasmic C-terminal tail of PC-1 can be cleaved by γ-secretase and relocated to the nucleus to induce the transcription of genes that promote cell survival. Specifically, we have demonstrated that the cytoplasmic C-terminal tail can induce transcription of cell survival genes such as STAT3. This process may lead to renal cysts. Here we attempt to show that the transcriptional ability of the C-terminal fragment of PC-1 may additionally be regulated by phosphorylation in the nucleus. This phosphorylation would allow the C-terminal fragment to be cleaved by caspases, thus disrupting its transcriptional ability. By this process, healthy cells are capable of regulating cell survival and apoptosis signals in a rheostat-like manner. In PKD, we propose that mutations in PKD1 disturb the balance between cell survival and apoptosis, resulting in cyst formation in either extreme.