Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity.
The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identification of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and sufficient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxia-inducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression.
Blankenship
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Department of Functional Genomics, Genome Therapeutics Corporation, Waltham, Massachusetts 02154, USA.
Naglich
J G
JG
Whaley
J M
JM
Seizinger
B
B
Kley
N
N
D000818:Animals; D019556:COS Cells; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D003062:Codon / Q000235:genetics*; D044842:Cullin Proteins; D000075065:Elongin; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D005807:Genes, Overlapping; D016147:Genes, Tumor Suppressor; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008025:Ligases; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C105153:CUL2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003062:Codon; D044842:Cullin Proteins; C000616396:ELOB protein, human; C000616395:ELOC protein, human; C000616401:Elob protein, mouse; C000616411:Eloc protein, mouse; D000075065:Elongin; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D011506:Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human; D013755:Tetradecanoylphorbol Acetate