Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein.

Abstract

Incubation in vitro of recombinant wild-type murine p53 protein with S-nitroso-N-acetyl-DL-penicillamine [a nitric oxide (NO)-releasing compound] has resulted in a change of p53 conformation and also in a significant decrease of its specific DNA binding activity. Similarly, upon treatment with S-nitroso-N-acetyl-DL-penicillamine (2-5 mM) or S-nitroso-glutathione (1-2 mM), human breast cancer cells (MCF-7), which express wild-type p53, rapidly accumulated p53 protein in the nuclei. This p53 protein, however, possessed a significantly decreased activity of specific DNA binding. On the other hand, lower concentrations of NO donors (0.25-0.5 mM) stimulated p53 accumulation as well as its DNA binding activity. These results suggest that excess NO produced in inflamed tissues could play a role in carcinogenesis by impairing the tumor suppressor function of p53.