Activator protein 1 (AP-1)- and nuclear factor kappa B (NF-kappa B)-dependent transcriptional events in carcinogenesis

Generation of reactive oxygen species (ROS) during metabolic conversion of molecular oxygen imposes a constant threat to aerobic organisms. Other than the cytotoxic effects, many ROS and oxidants are also potent tumor promote rs linking oxidative stress to carcinogenesis. Clonal variants of mouse epi dermal JB6 cells originally identified for their differential susceptibilit y to tumor promoters also show differential reduction-oxidation (redox) res ponses providing a unique model to study oxidative events in tumor promotio n. AP-1 and NF-kappa B, inducible by tumor promoters or oxidative stimuli, show differential protein levels or activation in response to tumor promote rs in JB6 cells. We further demonstrated that AP-1 and NF-kappa B are both required for maintaining the transformed phenotypes where inhibition of eit her activity suppresses transformation response in JB6 cells as well as hum an keratinocytes and transgenic mouse. NF-kappa B proteins or extracellular signal-regulated kinase (ERK) but not AP-1 proteins are shown to be suffic ient for conversion from transformation-resistant to transformation-suscept ible phenotype. Insofar as oxidative events regulate AP-1 and NF-kappa B tr ansactivation, these oxidative events can be important molecular targets fo r cancer prevention. (C) 2000 Elsevier Science Inc.