Increased expression of the proliferin gene family occurs upon exposure of C3H10T1/2 cells to a broad range of chemical agents known to promote morphological transformation and likely to increase cellular reactive oxygen species. To determine if proliferin gene expression is influenced by reactive oxygen species, superoxide radicals were generated in culture by the xanthine/xanthine oxidase couple. The 1 kb cytoplasmic proliferin transcript accumulated up to ten-fold following extracellular superoxide production. Within certain concentration ranges of catalase and superoxide dismutase activity, xanthine oxidase-induced proliferin expression was reduced to control levels, while expression was increased at other concentrations. Induction of proliferin by the tumour promoters butylated hydroxytoluene or TPA was efficiently inhibited at certain concentrations of catalase and superoxide dismutase, but retinoic acid had no effect. Proliferin induction by a recently identified promoter of transformation, tri-n-butyltin chloride, was stimulated by catalase, superoxide dismutase and retinoic acid, but inhibited at higher concentrations of N-acetyl cysteine. c-fos preceded proliferin induction by butylated hydroxytoluene, but several other oncogenes and growth-regulated genes were unaffected. The results support a mechanism for tumour promoter-induced proliferin gene expression that involves a response to superoxide anions, hydrogen peroxide or other shifts in the cellular equilibrium between pro-oxidant and anti-oxidant moieties.

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