Nitric oxide prevents gamma-radiation-induced cell cycle arrest by impairing p53 function in MCF-7 cells.
We previously reported that nitric oxide (NO) released from S-nitrosoglutathione induces conformational change of the p53 tumor-suppressor protein that impairs its DNA-binding activity in vitro. We now demonstrate that MCF-7 cells preincubated in the presence of 0.5-1 mM S-nitrosoglutathione for 4 h before gamma-irradiation failed to arrest in the G1 phase of the cell cycle, whereas those gamma-irradiated without S-nitrosoglutathione exhibited a normal cell cycle arrest. The S-nitrosoglutathione-treated cells did not express the p53 target gene p21(waf-1) after gamma-irradiation, although p21(waf-1) was strongly expressed in cells irradiated in the absence of S-nitrosoglutathione. These results strongly suggest that NO impairs the function of p53 possibly via conformational change and/or amino acid modifications. On the other hand, cells incubated for 16 h in the presence of 1 mM S-nitrosoglutathione underwent apoptosis with accumulation of the pro-apoptotic protein Bax. This Bax accumulation, however, was shown to occur via a p53-independent pathway.
Unit of Endogenous Cancer Risk Factors, Group of Molecular Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon cedex 08, 69372, France
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Chazotte-Aubert
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Pluquet
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Hainaut
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Ohshima
D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002453:Cell Cycle / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D017931:DNA Primers; D005720:Gamma Rays; D005978:Glutathione / Q000031:analogs & derivatives* / Q000502:physiology; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology*; D009603:Nitroso Compounds; D026422:S-Nitrosoglutathione; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D009603:Nitroso Compounds; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005978:Glutathione