title: Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines.
abstract: There is evidence that reactive oxygen species (ROS) are important mediators of tumor promotion and progression. The molecular mechanisms involved in ROS-mediated signaling, however, are unclear at present. Using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as model physical and chemical carcinogens, we have malignantly progressed 308 cells, a papilloma-producing mouse keratinocyte cell line, and investigated the molecular alterations in the progressed phenotypes. In this study, we demonstrate that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo. We found increased Erk-1/2 and p38 MAP kinase activities to be important components of ROS-mediated signaling. The pro-oxidant state also contributed to constitutive elevation of AP-1, NFkappaB and cAMP response element transactivation in the malignant phenotype. Our data provide evidence for a functional role of elevated ROS levels in tumor progression and implicate Erk-1/2 and p38 MAP kinase activation in the malignant progression of mouse keratinocytes.
authors.affiliation: Department of Radiation Oncology, The University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.forename: S F
authors.initials: SF
authors.lastname: Rosenberger
authors.forename: G T
authors.initials: GT
authors.lastname: Bowden
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism*; D008769:Methylnitronitrosoguanidine / Q000008:administration & dosage; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D008769:Methylnitronitrosoguanidine; D020928:Mitogen-Activated Protein Kinases