Journal Article

Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors

Konstantin Salnikow, Won G. An, Giovanni Melillo, Mikhail V. Blagosklonny and Max Costa

in Carcinogenesis

Volume 20, issue 9, pages 1819-1823
Published in print September 1999 | ISSN: 0143-3334
Published online September 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.9.1819
Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors

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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-1α 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-1α proteins accumulated following exposure to Ni. The induction of HIF-1α 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-1α 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.

Keywords: CHE, Chinese hamster embryo fibroblasts; DFX, deferoxamine mesylate; FBS, fetal bovine serum; HIF-1, hypoxia-inducible factor; MOI, multiplicity of infection; VEGF, vascular-endothelial growth factor

Journal Article.  4360 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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