ACTIVATION OF TRANSCRIPTION FACTOR NF-KAPPA-B AND P38 MITOGEN-ACTIVATED PROTEIN-KINASE IS MEDIATED BY DISTINCT AND SEPARATE STRESS EFFECTORPATHWAYS

Mitogen-activated protein (MAP) kinases are important mediators of the cellular stress response. Here, we investigated the relationship betw een activation of the MAP kinase p38 and transcription factor NF-kappa B. Different forms of cellular stress were found to preferentially tr igger either p38 or NF-kappa B. Arsenite or osmotic stress potently ac tivated p38 but were ineffective in inducing NF-kappa B activation, Tu mor necrosis factor-alpha and hydrogen peroxide, in contrast, led to N F-kappa B activation but only modestly stimulated p38, The activation of NF-kappa B was strongly abolished by antioxidants, while the activi ty of p38 and transcription factor AP-1 were increased, Inhibition of small GTPases including Rac and Cdc42 prevented p38 and AP-1 activatio n without interfering with NF-kappa B. In addition, inhibition of p38 by a pharmacological inhibitor or a dominant-negative mutant of MAP ki nase kinase-6, an activator of the p38 pathway, interfered with NF-kap pa B-dependent gene expression but not its DNA binding activity, Our r esults indicate that activation of p38 and NF-kappa B are mediated by separate pathways, which may converge further downstream in the cell n ucleus, Different forms of cellular stress, however, initially trigger distinct signaling cascades involving either oxidative stress or GTPa se coupled pathways.