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 neu ral cell killing. NO or the products of its redox chemistry can cause DNA damage and activate subsequent lethal reactions including energy d epletion and cell necrosis. However, regardless of whether it is endog enously produced in response to cytokines, or generated by chemical br eakdown 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 t umor suppressor gene, p53, in RAW 264.7 macrophages or pancreatic RINm 5F cells prior to apoptosis. NO-synthase inhibitors such as NG-monomet hyl-L-arginine prevent the inducible NO generation as well as p53 expr ession and apoptosis. Since p53 expression is linked to apoptosis in s ome cells exposed to DNA damaging agents, we suggest that NO-induced a poptosis in these cell systems is the consequence of DNA damage and su bsequent expression of this tumor suppressor gene.