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

Nickel (Ni) compounds are potent carcinogens and can induce malignant trans formation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional ac tivity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells, We demonstrated that the activity of HIF-1-respon sive promoters was increased in Ni-transformed rodent cells resulting in th e increased ratio between HIF-1- and p53-stimulated transcription. To furth er elucidate the roles of HIF-1 and p53 in Ni-induced transformation we use d human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cell s. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1 alpha 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-1 alpha proteins accumulated followi ng exposure to Ni, The induction of HIF-1 alpha 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-1 alpha protein and simu ltaneous accumulation of wild-type, but not mutant, p53. We suggest that th e induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-ind uced carcinogenesis.