The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat

Background: Stimuli that stress cells, including inflammatory cytokines, ultraviolet irradiation, DNA-damaging chemotherapeutic drugs and heat shock, stimulate a recently identified cytoplasmic signaling system that is structurally related to the mitogen-activated protein kinase pathway, This pathway consists of a cascade of protein kinases including stress-activated protein kinase (SAPK), also termed Jun N-terminal kinase (JNK), and two kinases that activate it, MEKK and SEK/MKK4, Despite rapid progress in delineating the components of this pathway, the cellular consequence of its activation remains to be defined. Results: We have screened cells for defects in SAPK signaling and identified a cell line, previously characterized for its thermotolerance properties, as being more refractive to SAPK activation induced by heat stress than its thermosensitive parental line, Stable expression of dominant inhibiting SEK mutants in thermosensitive parental cells specifically and effectively blocked SAPK activation after heat shock, These lines also became markedly resistant to the cytocidal effects of thermal stress, confirming the phenotype of the thermotolerant line, These cell lines defective in SAPK activation were also resistant to the lethal effects of the DNA-damaging drug cis-platinum. Conclusions: Experimentally induced stable blockade of SAPK activation in cells with normal thermosensitivity is sufficient to confer resistance to cell death induced by diverse stimuli including heat and the chemotherapeutic agent cisplatinum. These results suggest that activation of the SAPK pathway by diverse cell stressors plays a critical part in mediating the toxicity of these treatments and inducing cell death. SAPK activation in this context could broadly influence cellular response to stress, modulate apoptosis during development or determine the clinical response of tumor cells to cytotoxic therapies.