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-nitrosoglutat hione induces conformational change of the p53 tumor-suppressor protein tha t 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 cyc le, 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 p 21(waf-1) was strongly expressed in cells irradiated in the absence of S-ni trosoglutathione. These results strongly suggest that NO impairs the functi on of p53 possibly via conformational change and/or amino acid modification s. On the other hand, cells incubated for 16 h in the presence of 1 mM S-ni trosoglutathione underwent apoptosis with accumulation of the pro-apoptotic protein Bax. This Bax accumulation, however, was shown to occur via a p53- independent pathway. (C) 2001 Academic Press.