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Primary Cilium Formation Requires von Hippel-Lindau Gene Function in Renal-Derived Cells

Departments of ¹ Microbiology and Immunology, ² Pediatrics, and ³ Epidemiology and Social Medicine, Marion Bessin Liver Research Center and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: Robert D. Burk, Ullmann Building, Room 515, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: 718-430-3720; Fax: 718-430-8975; E-mail: burk{at}aecom.yu.edu.

Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, occurs in the majority of renal clear cell carcinomas (RCC). VHL's function, regulating the degradation of hypoxia-inducible factor (HIF) subunits, explains the angiogenic nature of these tumors, but not tumor initiation. Because the development of renal cysts precedes tumor formation, and because the dysfunction of primary cilium is a common pathogenic mechanism in polycystic kidney diseases, we determined whether kidney-derived VHL– cells required VHL for the generation of cilium. Ectopic expression of VHL in RCC(VHL–) cells induced increased polarization and primary cilium formation. Cilium formation correlated directly with the expression of both wild-type VHL isoforms and a VHL mutant not associated with RCC development, whereas expression of RCC-associated VHL mutants did not support ciliogenesis. Requirement of VHL for ciliogenesis was independent of HIF abundance. These data indicate separable independent functions for VHL (HIF degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis. (Cancer Res 2006; 66(14): 6903-07)

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