Oxidant carcinogenesis and antioxidant defense.
Growth promotion by oxidants is observed with cultured human and mouse fibroblasts as well as epidermal cells. It is expected to play a role in inflammation, fibrosis, and tumorigenesis. Indeed, oxidants trigger (patho)physiological reactions that resemble those induced by growth and differentiation factors. For example, active oxygen activates protein kinases, causes DNA breakage, and induces the growth competence-related protooncogenes c-fos and c-myc. The cellular antioxidant defenses affect the consequences of oxidant exposure. Transfectants of mouse epidermal cells that overproduce Cu,Zn-superoxide dismutase (SOD) were sensitized to the toxic effects of an extracellular burst of O2-. plus H2O2, whereas overproducers of catalase (CAT) were protected. Transfection of SOD overproducers with CAT corrected their hypersensitivity. Inducibility of the protooncogene c-fos by oxidants was diminished in SOD and CAT overproducers, albeit probably for different reasons. It is concluded that a fine balance of the multiple components of the antioxidant defense determines the growth response of cells to oxidative stress. In studies of the mechanism of the transcriptional induction of c-fos by oxidants, we identified the joint DSE-AP1 elements (dyad symmetry element, DSE) as major enhancer motifs in the 5'-upstream regulatory sequences of c-fos. Oxidants also increased the de novo synthesis of protein factors that bind to the fos-AP1 enhancer motif. Protein kinase and ADPR transferase inhibitors suppressed the transcriptional induction of c-fos as well as the increase in factor binding to fos-AP1. We conclude that protein phosphorylation and protein polyADP-ribosylation are required for the transcriptional induction of c-fos and the synthesis of protein factors that bind to fos-AP1. It is likely that the FOS and JUN proteins are among these factors and that they participate in the regulation of c-fos expression by oxidants.
Cerutti
P
P
Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Epalinges/Lausanne.
Shah
G
G
Peskin
A
A
Amstad
P
P
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D002374:Catalase / Q000378:metabolism; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D000078404:Epidermal Cells; D016762:Genes, fos; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D016877:Oxidants / Q000633:toxicity*; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D004268:DNA-Binding Proteins; D016877:Oxidants; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D004247:DNA; D002374:Catalase; D013482:Superoxide Dismutase