NITRIC-OXIDE MODULATES THE C-JUN N-TERMINAL KINASE STRESS-ACTIVATED PROTEIN-KINASE ACTIVITY THROUGH ACTIVATING C-JUN N-TERMINAL KINASE KINASE

Nitric oxide is a signaling molecule that has a broad range of physiol ogical functions, including neurotransmission, macrophage activation, and vasodilation. The mechanism by which nitric oxide regulates signal transduction mediating diverse biological activities is not fully und erstood, however. Here, we demonstrate that nitric oxide induced the s timulation of c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase (SAPK) in intact cells. Exposure of cultured HEK293 cells to s odium nitroprusside, a nitric oxide releasing agent, resulted in the s timulation of JNK1 activity. The sodium nitroprusside-induced stimulat ion of JNK1 activity was abolished by treatment of cells with N-acetyl cysteine. Nitric oxide production from HEK293 cells ectopically expres sing nitric oxide synthases resulted in the stimulation of JNK1 activi ty, while JNK1 stimulation in nitric oxide synthase-overexpressing cel ls was abrogated by a nitric oxide synthase inhibitor, N-G-nitro-L-arg inine. Furthermore, exposure of cells to sodium nitroprusside resulted in the stimulation of JNK kinase (JNKK1/SEK1). Taken together, our da ta suggest that nitric oxide modulates the JNK activity through activa ting JNKK1/SEK1.