Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-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 promoters linking oxidative stress to carcinogenesis. Clonal variants of mouse epidermal JB6 cells originally identified for their differential susceptibility to tumor promoters also show differential reduction-oxidation (redox) responses providing a unique model to study oxidative events in tumor promotion. AP-1 and NF-kappaB, inducible by tumor promoters or oxidative stimuli, show differential protein levels or activation in response to tumor promoters in JB6 cells. We further demonstrated that AP-1 and NF-kappaB are both required for maintaining the transformed phenotypes where inhibition of either activity suppresses transformation response in JB6 cells as well as human keratinocytes and transgenic mouse. NF-kappaB proteins or extracellular signal-regulated kinase (ERK) but not AP-1 proteins are shown to be sufficient for conversion from transformation-resistant to transformation-susceptible phenotype. Insofar as oxidative events regulate AP-1 and NF-kappaB transactivation, these oxidative events can be important molecular targets for cancer prevention.
Hsu
T C
TC
IRSP, SAIC-Frederick, Frederick, MD, USA.
Young
M R
MR
Cmarik
J
J
Colburn
N H
NH
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D002999:Clone Cells / Q000187:drug effects; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000633:toxicity; D004817:Epidermis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000633:toxicity
D051017:Apoptosis Regulatory Proteins; D002273:Carcinogens; D016328:NF-kappa B; D009363:Neoplasm Proteins; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate