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

  • Chapter
Oxygen/Nitrogen Radicals: Cell Injury and Disease

Part of the book series: Developments in Molecular and Cellular Biochemistry ((DMCB,volume 37))

Abstract

Generation of reactive oxygen species (ROS) stimulates transcription by activating transcription factors activator protein 1 (AP-1) and nuclear factor KB (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-a), as well as oxidative stress. TPA and EGF, acting through the MAP kinase pathway, activate AP-1 and subsequently NF-KB proteins and downstream transcription processes that are involved in the transformation response in transformation-sensitive (P+) JB6 cells. The effect of TNF-a is primarily on the NF-KB pathway. ROS and other free radicals can activate AP-1 and NF-KB transcription coordinately. In JB6 cells, both ERK/Fra-1 and NF-KB activity is essential for the transformation response. Inhibition of NF-KB 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-KB 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. (Mol Cell Biochem 234/235: 185–193, 2002)

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  1. Gene Regulation Section, National Cancer Institute at Frederick, Frederick, MD, USA

    Arindam Dhar, Mathew R. Young & Nancy H. Colburn

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  1. Arindam Dhar
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  1. Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road Mall Stop B167, Morgantown, WV, 26505, USA

    Val Vallyathan , Xianglin Shi Ph.D.  & Vince Castranova ,  & 

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Dhar, A., Young, M.R., Colburn, N.H. (2002). The role of AP-1, NF-кB and ROS/ NOS in skin carcinogenesis: The JB6 model is predictive. In: Vallyathan, V., Shi, X., Castranova, V. (eds) Oxygen/Nitrogen Radicals: Cell Injury and Disease. Developments in Molecular and Cellular Biochemistry, vol 37. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1087-1_21

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