title: Common and distinct mechanisms of different redox-active carcinogens involved in the transformation of mouse JB6P+ cells.
abstract: We transformed JB6P+ cells with prolonged intermittent low-dose UVB radiation or prolonged exposure to low-dose H(2)O(2) or CdCl(2). Stable transformation was confirmed by an anchorage-independence assay. The JB6P+ transformants formed more colonies (approximately six folds) in soft agar as compared to their JB6P+ parent cells and were associated with increased intracellular reactive oxygen species (ROS) levels. Activating protein-1 (AP-1) is a family of transcription factors that are rapidly activated by elevated intracellular ROS levels, and their composition is important in the process of cellular transformation and/or tumor progression. To investigate if carcinogenesis induced by distinct carcinogens was via similar molecular mechanisms in these transformants, gel mobility shift and immunoblot analyses were utilized to determine the distinct AP-1 compositions. Compared to parent JB6P+ cells, the gain of JunB and Fra-1 in AP-1 DNA binding complexes was markedly increased in all transformed cells, which might contribute to a more proliferative phenotype, while loss of Fra-2 occurred in JB6P+/H(2)O(2) and JB6P+/Cd cells. Differential AP-1 components in the transformants suggested that their transformations might be mediated by distinct transcription signalings with distinct AP-1 dimer compositions. However, all three transformants exhibited increased activation of pathways involved in cell proliferation (ERK/Fra-1/AP-1 and JNK/c-jun/AP-1) and anti-apoptosis (Bcl-xl). The development of the JB6P+ transformants (JB6P+/UVB; JB6P+/H(2)O(2); JB6P+/Cd) provides a unique tool to study the mechanisms that contribute to different redox-active carcinogens in a single model.
authors: Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California 92868, USA.
authors: Sun
authors: S
authors: Yang
authors: Bobbye
authors: B
authors: Misner
authors: Rita
authors: R
authors: Chiu
authors: Frank L
authors: FL
authors: Meyskens
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019256:Cadmium Chloride / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D051921:Fos-Related Antigen-2 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D000099169:Fos-Related Antigen 1
chemical_list: D019256:Cadmium Chloride; D002273:Carcinogens; D051921:Fos-Related Antigen-2; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D016877:Oxidants; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C497873:Fosl2 protein, mouse