Molecular alchemy of the tumor suppressor protein p53:: Metals and cell growth control

The p53 protein is an ubiquitous multifunction, zinc-binding transcription factor that is activated in response to multiple forms of stress and that controls proliferation, survival, DNA repair, and differentiation of cells exposed to potentially genotoxic DNA-damage. Loss of p53 function by mutation is a frequent event in human cancer. The sequence-specific DNA-binding domain of p53 is stabilized by the coordination of an atom of zinc within a Cys3His1 cluster. Zinc removal using metal chelators alters p53 conformation and abrogates specific DNA-binding in vitro and in cultured cells. In intact cells, p53 protein activity is dependent upon the availability of zinc ions and is impaired by exposure to cadmium, a metal that readily substitutes for zinc in a number of transcription factors. Inactivation by cadmium suppresses the p53-dependent responses to DNA-damage. These data indicate that regulation by metals may play an important role in the control of p53. Perturbation of this control may contribute to the carcinogenic potential of several metal compounds. J. Trace Elem. Exp. Med. 12:337-346, 1999. (C) 1999 Wiley-Liss, Inc.