Primary cilium formation requires von Hippel-Lindau gene function in renal-derived cells

Mallory S. Lutz, Robert D. Burk

Research output: Contribution to journalArticle

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Abstract

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 α (HIFα) 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 HIFα abundance. These data indicate separable independent functions for VHL (HIFα degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)6903-6907
Number of pages5
JournalCancer Research
Volume66
Issue number14
DOIs
StatePublished - Jul 15 2006

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Cilia
Renal Cell Carcinoma
Kidney
Genes
Polycystic Kidney Diseases
Neoplasms
Tumor Suppressor Genes
Cysts
Protein Isoforms
Carcinogenesis
Hypoxia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Primary cilium formation requires von Hippel-Lindau gene function in renal-derived cells. / Lutz, Mallory S.; Burk, Robert D.

In: Cancer Research, Vol. 66, No. 14, 15.07.2006, p. 6903-6907.

Research output: Contribution to journalArticle

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AB - 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 α (HIFα) 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 HIFα abundance. These data indicate separable independent functions for VHL (HIFα degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis.

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