Renal cell carcinoma- and pheochromocytoma-specific altered gene expression profiles in VHL mutant clones.
Von Hippel-Lindau (VHL) disease is associated with various missense germline mutations in the VHL tumor suppressor gene. Some are associated with type 1 VHL disease, renal cell carcinoma (RCC) without pheochromocytoma, while others are associated with type 2A or 2B VHL disease, pheochromocytoma without and with RCC, respectively. These mutations may cause substitutions of specific amino acid residue and functional change of VHL protein (pVHL), which leads to the oncogenesis of the particular tumor types that characterize the different VHL disease types. To investigate, we transfected a pVHL-null RCC cell line with plasmids expressing wild-type pVHL (WT) or pVHL bearing 1 of 3 point mutations. These occur in the pVHL regions that bind hypoxia-inducible factor alpha (HIF-alpha ) or Elongin C. Microarray analysis showed that the clones bearing a mutation in the elongin-binding region (mutant 167) were unique, as many more genes were suppressed than up-regulated. The other two mutant groups, which bear a mutation in the HIF-alpha -binding region (mutants 98 and 111), showed the opposite pattern. The 167 mutation is associated with type 2B VHL disease. Real-time PCR analysis confirmed the altered expression of selected genes in the clones. Relative to WT, stratifin (14-3-3 sigma) and lysyl oxidase-like 1 were down-regulated in the 167 mutants, while the transforming growth factor beta-induced protein (beta ig-h3) was up-regulated in the 111 mutants. Thus, the location of pVHL mutations results in distinct gene expression patterns. Moreover, a mutation in the elongin-binding domain may induce type 2B tumors through different molecular pathways compared to those induced by type 1- or 2A-associated mutations in the HIF-alpha -binding region.
Tsuchiya
Mutsumi I
MI
Department of Urology, Kochi Medical School, Nankoku-city, Kochi 783-8505, Japan.
Okuda
Heiwa
H
Takaki
Yasuyuki
Y
Baba
Masaya
M
Hirai
Syu-Ichi
S
Ohno
Shigeo
S
Shuin
Taro
T
D000310:Adrenal Gland Neoplasms / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075065:Elongin; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010673:Pheochromocytoma / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C000616395:ELOC protein, human; D000075065:Elongin; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human