TY - JOUR
T1 - HIF activation defines early lesions in VHL kidneys: Evidence for site specific tumour suppressor function in the nephron
AU - Mandriota, SJ
AU - Turner, KJ
AU - Davies, DR
AU - Murray, Paul
AU - Morgan, Neil
AU - Sowter, HM
AU - Wykoff, CC
AU - Maher, Eamonn
AU - Harris, AL
AU - Ratcliffe, PJ
PY - 2002/6/1
Y1 - 2002/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=17044452288&partnerID=8YFLogxK
U2 - 10.1016/S1535-6108(02)00071-5
DO - 10.1016/S1535-6108(02)00071-5
M3 - Article
C2 - 12124175
VL - 1
SP - 459
EP - 468
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -