The role of AP-1, NF-kappaB and ROS/NOS in skin carcinogenesis: the JB6 model is predictive

Abstract

Generation of reactive oxygen species (ROS) stimulates transcription by activating transcription factors activator protein 1 (AP-1) and nuclear factor kappaB (NF-KB). The mouse epidermal JB6 cells constitute a model system that has significantly contributed to the understanding of these events. Clonal variants of JB6 cells are differentially responsive to transformation induced by tumor promoters such as phorbol esters (TPA), epidermal growth factor (EGF) and tumor necrosis factor alpha (TNF-alpha), as well as oxidative stress. TPA and EGF, acting through the MAP kinase pathway, activate AP-1 and subsequently NF-kappaB proteins and downstream transcription processes that are involved in the transformation response in transformation-sensitive (P+) JB6 cells. The effect of TNF-alpha is primarily on the NF-kappaB pathway. ROS and other free radicals can activate AP-1 and NF-KB transcription coordinately. In JB6 cells, both ERK/Fra-1 and NF-kappaB activity is essential for the transformation response. Inhibition of NF-kappaB and AP-1 activity abrogates transformation in JB6 cells as well as in transgenic mice and human keratinocytes. A similar effect is seen with antioxidants, which inhibit NF-kappaB and AP-1 activity as well as transformation in JB6 cells. The JB6 model is therefore valuable for monitoring early events in oxidative stress related signaling leading to carcinogenesis, and for identifying molecular targets for cancer chemoprevention.