Journal
CANCER RESEARCH
Volume 66, Issue 14, Pages 6903-6907Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-0501
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- NCI NIH HHS [CA85412] Funding Source: Medline
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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 alpha (HIF alpha) 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 WE 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 alpha abundance. These data indicate separable independent functions for VHL (HIF alpha degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis.
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