NITRIC OXIDE-INDUCED P53 ACCUMULATION AND REGULATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION BY WILD-TYPE P53

The tumor suppressor gene product p53 plays an important role in the c ellular response to DNA damage from exogenous chemical and physical mu tagens. Therefore, we hypothesized that p53 performs a similar role in response to putative endogenous mutagens, such as nitric oxide (NO). We report here that exposure of human cells to NO generated from an NO donor or from overexpression of inducible nitric oxide synthase (NOS2 ) results in p53 protein accumulation, In addition, expression of wild -type (WT) p53 in a variety of human tumor cell lines, as well as muri ne fibroblasts, results in down-regulation of NOS2 expression through inhibition of the NOS2 promoter, These data are consistent with the hy pothesis of a negative feedback loop in which endogenous NO-induced DN A damage results in WT p53 accumulation and provides a novel mechanism by which p53 safeguards against DNA damage through p53-mediated trans repression of NOS2 gene expression, thus reducing the potential for NO -induced DNA damage.