OVEREXPRESSION OF MANGANESE SUPEROXIDE-DISMUTASE SUPPRESSES TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS AND ACTIVATION OF NUCLEAR TRANSCRIPTIONFACTOR-KB AND ACTIVATED PROTEIN-1

Several recently identified intracellular proteins associate with the tumor necrosis factor (TNF) receptor and activate nuclear transcriptio n factor (NF)-kappa B, c-Jun kinase, and apoptosis. However, the mecha nism is not understood. In the present report, we investigated the rol e of reactive oxygen intermediates in TNF-induced signaling. Overexpre ssion of manganese superoxide dismutase (Mn-SOD) in human breast cance r MCF-7 cells completely abolished TNF-mediated NF-kappa B activation, I kappa B alpha degradation, p65 nuclear translocation, and NF-kappa B-dependent reporter gene expression. Besides TNF, phorbol ester-, oka daic acid-, ceramide-, and lipopolysaccharide-induced activation of NF -kappa B was blocked by Mn-SOD, indicating a common pathway of activat ion. H2O2-induced NF-kappa B activation, however, was potentiated. In addition, Mn-SOD blocked the TNF-mediated activation of activated prot ein-1, stress-activated c-Jun protein kinase, and mitogen-activated pr otein kinase kinase. TNF-induced antiproliferative effects and caspase -3 activation, indicators of apoptosis, were also completely suppresse d by transfection of cells with Mn-SOD. Suppression of apoptosis induc ed by okadaic acid, H2O2, and taxol was also inhibited by Mn-SOD but n ot that induced by vincristine, vinblastine, or daunomycin. Overall, t hese results demonstrate that, in addition to several recently identif ied signaling molecules, reactive oxygen intermediates play a critical role in activation of NF-kappa B, activated protein-1, c-Jun kinase, and apoptosis induced by TNF and other agents.