(Taken directly from the application) Polycystic kidneys are generally described as abnormally differentiated. Our long term goal is to understand how mutations in PKD1 result in this abnormally differentiated state and lead to the loss of renal function. Polycystin-1, the protein product of the PKD1 gene, is thought to be a plasma membrane receptor that mediates signal transduction events and thereby regulates gene expression associated with the acquisition and/or maintenance of the terminally differentiated state of renal epithelial cells. One family of genes whose renal expression is associated with a differentiated phenotype and whose expression has been shown to be aberrant in cystic kidneys is that encoding the xenobiotic-metabolizing glutathione S-transferase (GST) enzymes. Our new preliminary data demonstrates that the glucocorticoid (GC)-inducible expression of the endogenous GST-Ya gene is enhanced by expression of a membrane-directed polycystin fusion protein in a stably transfected renal epithelial cell line. GCs are involved in the regulation of cell growth and differentiation. Most of the effects of GCs are mediated by the ligand-activated glucocorticoid receptor (GR) that functions as a transcriptional regulator whose activity is affected by phosphorylation. Polycystin activates JNK and inhibits GSK-3, two kinases known to phosphorylate GR Taken together, these data suggest that polycystin could regulate signal transduction pathways that modulate the activity of GR and thereby result in augmentation of the GC-induced expression of the GST-Ya gene. Cross-talk between polycystin-mediated signaling pathways and the GC response pathway may represent a general mechanism by which polycystin influences the differentiated state of renal epithelial cells and may prove to be particularly relevant to some of the pathogenetic mechanisms associated with polycystic kidney disease. This project will utilize the GST-Ya gene promoter and its GC-induced expression as a model system in which to determine the role of polycystin in modulating GR-regulated functions. This objective will be addressed by the following Specific Aims: 1) determine the nuclear mechanism(s) by which polycystin modulates GC-induced GST-Ya gene expression; 2) determine the effect(s) of polycystin expression on GR activity; and 3) determine the signal transduction pathways and downstream effectors involved in polycystin modulation of GR function and GC-induced GST-Ya gene expression. This project is anticipated to lead to new insight into the mechanisms by which polycystin affects renal tubular differentiation and prevents the loss of renal function in PKD.
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