Summary
Oxidants can act at several stages of tumorigenesis. They produce heritable changes in DNA structure ad may play a role in the mutational activation or inactivation of cancer related genes. Mutations in these genes in general do not produce a selectable cellular phenotype. Therefore, we have developed the RFLP/PCR protocol (RFLP, restriction fragment lenght polymorphism; PCR, polymerase chain reaction) for the “genotypic” analysis of oxidant-induced base pair changes in hotspot codons of the human H-ras protooncogene and the p53 tumor suppressor gene. 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 which resemble those induced by growth- and differentiation factors. They activate protein kinases, cause DNA breakage and induce the growth competence related protooncogenes c-fos, c-jun and c-myc. Mechanistic studies indicate that protein-phosphorylation and -polyADP-rybosilation are required for the transcriptional induction of c-fos by oxidants and the synthesis of protein factors, including FOS- and JUN-proteins, which bind to the fos-AP1 enhancer element. PolyADPR participates in the efficient repair of DNA breakes which otherwise may retard or block transcriptional elongation. A fine balance of the multiple components of the cellular antioxidant defence determines the growth response of cells to oxidative stress. Transfectants of mouse epidermal cells which overproduce Cu,Zn-SOD were sensitized to the toxic effects of an oxidant while overproducers of catalase (CAT) were protected.
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Cerutti, P., Shah, G., Peskin, A., Amstad, P. (1993). Molecular Mechanisms Of Oxidant Carcinogenesis. In: Poli, G., Albano, E., Dianzani, M.U. (eds) Free Radicals: from Basic Science to Medicine. Molecular and Cell Biology Updates. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-9116-5_18
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