A role for the Na/K-ATPase in the control of human c-fos and c-jun transcription.

The c-fos proto-oncogene is known to be regulated by a variety of hormones, growth factors, and other conditions that alter cellular metabolism. The regulation of c-fos RNA concentrations is known to occur both by altered RNA half-life and/or changes in the transcription rate of the gene. In most cases thus far investigated, induction of c-fos transcription by growth factors occurs very rapidly and transiently. Results presented in this paper show that ouabain, a specific inhibitor of the Na/K-ATPase increases the transcription of c-fos, as well as c-jun, in a variety of cultured cells. However, in contrast to other agents that induce c-fos and c-jun expression, the increased transcription rate of these genes in the presence of ouabain required several hours and remained elevated for at least 16 h. NIH 3T3 cells that have been transfected with deletions of the human c-fos promoter have enabled us to define at least two elements within the promotor that are regulated by ouabain. These include the serum response element and a region between 123 and 222 base pairs 5' to the start site of transcription. We speculate that regulation of the intracellular ion balance through changes in Na/K pump activity may be a general mechanism by which basal transcriptional activity of c-fos is modulated.