HIF activation identifies early lesions in VHL kidneys: Evidence for site-specific tumor suppressor function in the nephron

Stefano J. Mandriota, Kevin J. Turner, David R. Davies, Paul G. Murray, Neil V. Morgan, Heidi M. Sowter, Charles C. Wykoff, Eamonn R. Maher, Adrian L. Harris, Peter J. Ratcliffe, Patrick H. Maxwell

Research output: Contribution to journalArticle

383 Scopus citations

Abstract

Mutations in the von Hippel-Lindau (VHL) gene are associated with hereditary and sporadic clear cell renal carcinoma. VHL acts in a ubiquitin ligase complex regulating hypoxia-inducible factor-1 (HIF-1), but the link between this function and cancer development is unclear. Here we show that in the kidneys of patients with VHL disease, HIF activation is an early event occurring in morphologically normal single cells within the renal tubules. In comparison, dysplastic lesions, cystic lesions, and tumors showed evidence of additional mechanisms that amplify HIF activation. Detection of cells with constitutive HIF activation identified a large number of previously unrecognized foci of VHL inactivation. In proximal tubules these were almost entirely unicellular, whereas multicellular foci were almost exclusively seen in the distal nephron.

Original languageEnglish (US)
Pages (from-to)459-468
Number of pages10
JournalCancer Cell
Volume1
Issue number5
DOIs
StatePublished - Jun 2002

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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