Abstract
Inactivation of the von Hippel-Lindau tumor suppressor gene is linked to the development of hereditary (VHL Disease-associated) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, targets the heterodimeric transcription factor HIF for polyubiquitination, and restoration of pVHL function in VHL(-/-) renal carcinoma cells suppresses their ability to form tumors in nude mice. Here we show that tumor suppression by pVHL can be overridden by a HIF variant that escapes pVHL control. These studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Carcinoma, Renal Cell / genetics*
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Cycloheximide / pharmacology
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Down-Regulation
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Genes, Tumor Suppressor / physiology*
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Glucose Transporter Type 1
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Humans
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Immunoenzyme Techniques
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Kidney Neoplasms / genetics*
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Ligases / physiology*
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Mice
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Mice, Nude
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Monosaccharide Transport Proteins / metabolism
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Mutation
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Plasmids
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Protein Synthesis Inhibitors / pharmacology
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Retroviridae / genetics
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics*
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
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Ubiquitin-Protein Ligases*
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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Glucose Transporter Type 1
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Monosaccharide Transport Proteins
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Protein Synthesis Inhibitors
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SLC2A1 protein, human
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Transcription Factors
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Tumor Suppressor Proteins
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Cycloheximide
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Ligases
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VHL protein, human