Title: Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors.
Authors: Salnikow, K; An, W G; Melillo, G; Blagosklonny, M V; Costa, M
Published In Carcinogenesis, (1999 Sep)
Abstract: 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.
PubMed ID: 10469629
MeSH Terms: 3T3 Cells/drug effects; Adenocarcinoma/pathology; Animals; Bone Neoplasms/pathology; Breast Neoplasms/pathology; Bronchi/cytology; Cadmium Chloride/toxicity; Carcinogens, Environmental/toxicity*; Cell Hypoxia; Cell Transformation, Neoplastic/drug effects*; Cobalt/toxicity; Cricetinae; Cricetulus; DNA-Binding Proteins/metabolism*; Epithelial Cells/drug effects; Fibroblasts/drug effects; Gene Expression Regulation/drug effects*; Genes, p53; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms/pathology; Mice; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Nickel/toxicity*; Nuclear Proteins/metabolism*; Osteosarcoma/pathology; Promoter Regions, Genetic; Recombinant Fusion Proteins/metabolism; Transcription Factors*; Transcription, Genetic/drug effects*; Tumor Cells, Cultured; Tumor Suppressor Protein p53/metabolism*