Roles of TSC1 TDC2 and Rheb in renal cyst pathogenesis

Fox Chase Cancer Center, Philadelphia PA

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Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutation in either the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) gene, in which severe renal cystic disease can occur. Links have been identified between tuberin (TSC2), and polycystin 1 (PC1), the product of the polycystic kidney disease 1 (PKD1) gene. Many proteins associated with renal cystic disease are localized to the primary cilium of renal epithelial cells. It is believed that aberrant ciliary function plays a central role in cyst pathogenesis. We have found that endogenous hamartin is centrosome-localized. Since the centrosome gives rise to the basal body of the primary cilium, this may link TSC with the cilium and with renal cystic diseases. Our central hypothesis is that activation of TSC-dependent pathways is a key determinant of renal cyst pathogenesis. We will determine (1) if TSC proteins localize to the basal body or effect localization of PC1 to the cilia, (2) if TSC pathways regulate centrosome number or formation of functional cilia, (3) if upregulation of TSC pathways induce cyst formation in a mouse model. These are crucial steps toward the design of targeted therapeutic strategies for cystic disease in TSC and ADPKD.