NITRIC-OXIDE INDUCES CONFORMATIONAL AND FUNCTIONAL MODIFICATIONS OF WILD-TYPE P53 TUMOR-SUPPRESSOR PROTEIN

Incubation in vitro of recombinant wild-type murine p53 protein with S -nitroso-N-acetyl-DL-penicillamine [a nitric oxide (NO)-releasing comp ound] has resulted in a change of p53 conformation and also in a signi ficant decrease of its specific DNA binding activity, Similarly, upon treatment with S-nitroso-N-acetyl-DL-penicillamine (2-5 mM) or S-nitro so-glutathione (1-2 mM), human breast cancer cells (MCF-7), which expr ess 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 d onors (0.25-0.5 mM) stimulated p53 accumulation as well as its DNA bin ding activity, These results suggest that excess NO produced in inflam ed tissues could play a role in carcinogenesis by impairing the tumor suppressor function of p53.