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Molecular Biology and Genetics |
Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health [M. Z., N. F. d. S., S. C. C., M. R. M., F. M. R., F. L., E. R. M.] and Cancer Research Campaign Renal Molecular Oncology Research Group [N. F. d. S., M. R. M., F. M. R., F. L., E. R. M.], University of Birmingham, The Medical School, Birmingham B15 2TT, United Kingdom; Department of Nephrology and Medical Intensive Care, Charité, Humboldt-University, 13353 Berlin, Germany [M. S. W., K-U. E.]; and Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom [R. S. H.]
Germ-line mutations in the von Hippel-Lindau (VHL) tumor suppressor disease are associatedwith a high risk of retinal and cerebellar hemangioblastomas, renalcell carcinoma (RCC), and, in some cases, pheochromocytoma (PHE). In addition, somatic mutation or epigenetic inactivation of the VHL gene occurs in most clear cell RCCs. VHL protein (pVHL) has a critical role in regulating proteasomal degradation of the HIF transcription factor, and VHL inactivation results in overexpression of many hypoxia-inducible mRNAs including vascular endothelial growth factor (VEGF). To identify novel pVHL target genes we investigated the effect of wild-type (WT) pVHL on the expression of 588 cancer-related genes in two VHL-defective RCC cell lines. Expression array analysis identified nine genes that demonstrated a >2-fold decrease in expression in both RCC cell lines after restoration of WT pVHL. Three of the nine genes (VEGF, PAI-1, and LRP1) had been reported previously as pVHL targets and are known to be hypoxia-inducible. In addition, six novel targets were detected: cyclin D1 (CCND1), cell division protein kinase 6, collagen VIII 
1 subunit, CD59 glycoprotein precursor, integrin ß8, and interleukin 6 precursor IFN-ß2. We found no evidence that CCND1, cell division protein kinase 6, CD59, and integrin ß8 expression was influenced by hypoxia suggesting that pVHL down-regulates these targets by a HIF-independent mechanism. A type 2C pVHL mutant (V188L), which is associated with a PHE only phenotype (and had been shown previously to retain the ability to promote HIF ubiquitylation), retained the ability to suppress CCND1expression suggesting that loss of pVHL-mediated suppression of cyclin D1 is not necessary for PHE development in VHL disease. Other studies have suggested that: (a) genetic modifiers influence the phenotypic expression of VHL disease; and (b) polymorphic variation at a CCND1 codon 242 A/G single nucleotide polymorphism (SNP) may influence cancer susceptibility or prognosis in some situations. Therefore, we analyzed the relationship between CCND1 genotype and phenotypic expression of VHL disease. There was an association between the G allele and multiple retinal angiomas (P = 0.04), and risk of central nervous system hemangioblastomas (P = 0.05). These findings suggest that a variety of HIF-independent mechanisms may contribute to pVHL tumor suppressor activity and that polymorphic variation at one pVHL target influences the phenotypic expression of VHL disease.
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