Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors.
Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional activity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells. We demonstrated that the activity of HIF-1-responsive promoters was increased in Ni-transformed rodent cells resulting in the increased ratio between HIF-1- and p53-stimulated transcription. To further elucidate the roles of HIF-1 and p53 in Ni-induced transformation we used human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cells. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1alpha protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1alpha proteins accumulated following exposure to Ni. The induction of HIF-1alpha and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h. These results suggest that acute Ni treatment causes accumulation of HIF-1alpha protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-induced carcinogenesis.
Salnikow
K
K
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, NY 10016 USA. salinkow@env.med.nyu.edu
An
W G
WG
Melillo
G
G
Blagosklonny
M V
MV
Costa
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M
D016475:3T3 Cells / Q000187:drug effects; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D001980:Bronchi / Q000166:cytology; D019256:Cadmium Chloride / Q000633:toxicity; D002274:Carcinogens, Environmental / Q000633:toxicity*; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003035:Cobalt / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D016158:Genes, p53; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D009687:Nuclear Proteins / Q000378:metabolism*; D012516:Osteosarcoma / Q000473:pathology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002274:Carcinogens, Environmental; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003035:Cobalt; C022838:nickel chloride; D009532:Nickel; C018021:cobaltous chloride; D019256:Cadmium Chloride