Carcinogenic nickel induces genes involved with hypoxic stress.
Carcinogenic nickel compounds alter the program of gene expression in normal cells and induce a pattern of gene expression similar to that found in nickel-induced cancers. Here we have demonstrated that nickel exposure induced hypoxic signaling pathways by inducing hypoxia-inducible transcription factor-1 (HIF-1), which mediated the induction of genes required by cells to survive hypoxia. We also show that a new gene, Cap43, is dependent upon HIF-1 because only HIF-1-proficient cells induced Cap43 when exposed to either hypoxia or nickel. We also show that glyceraldehyde-3-phosphate dehydrogenase, a gene induced by hypoxia through HIF-1, was similar to Cap43 in that it required HIF-1-proficient cells to be induced by either nickel or hypoxia. These data demonstrate that nickel exposure turns on signaling for hypoxic stress, which may be important in its carcinogenesis.
Salnikow
K
K
Nelson Institute of Environmental Medicine, and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York 10016, USA. salnikow@env.med.nyu.edu
Blagosklonny
M V
MV
Ryan
H
H
Johnson
R
R
Costa
M
M
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009532:Nickel / Q000633:toxicity*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D002118:Calcium; D002273:Carcinogens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D009532:Nickel; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse