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 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.
Calmels
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S
Unit of Endogenous Cancer Risk Factors, IARC, Lyon, France.
Hainaut
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P
Ohshima
H
H
D001943:Breast Neoplasms / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
D004273:DNA, Neoplasm; D009603:Nitroso Compounds; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D026423:S-Nitroso-N-Acetylpenicillamine; D005978:Glutathione; D010396:Penicillamine