p53 expression in nitric oxide-induced apoptosis.

Nitric oxide (NO) is a diffusible messenger involved in several patho-physiological processes including immune-mediated cytotoxicity and neural cell killing. NO or the products of its redox chemistry can cause DNA damage and activate subsequent lethal reactions including energy depletion and cell necrosis. However, regardless of whether it is endogenously produced in response to cytokines, or generated by chemical breakdown of donor molecules, NO can also induce apoptosis in different systems. Here, we report that NO generation in response to a cytokine induced NO-synthase or by NO donors stimulates the expression of the tumor suppressor gene, p53, in RAW 264.7 macrophages or pancreatic RINm5F cells prior to apoptosis. NO-synthase inhibitors such as NG-monomethyl-L-arginine prevent the inducible NO generation as well as p53 expression and apoptosis. Since p53 expression is linked to apoptosis in some cells exposed to DNA damaging agents, we suggest that NO-induced apoptosis in these cell systems is the consequence of DNA damage and subsequent expression of this tumor suppressor gene.