cAMP abrogates the p21(ras)-mitogen-activated protein kinase pathway in fibroblasts

The mechanism by which cAMP inhibits growth factor-induced DNA synthesis in fibroblasts is not understood. Here we show that in Rat-1 fibroblasts, cAMP-raising agents inhibit p21(ras)-mediated mitogen-activated protein (MAP) kinase activation induced by either epidermal growth factor or lysophosphatidic acid. Under the same conditions, however, epidermal growth factor- or lysophosphatidic acid-induced protein tyrosine phosphorylation, Ca²⁺ mobilization, and activation of Na⁺/H⁺ exchange are not attenuated. In ras-transformed Rat-1 cells, 8-bromo-cAMP rapidly deactivates constitutively active MAP kinase without reducing p21(ras)·GTP levels; long term 8-bromo-cAMP treatment of these cells leads to growth arrest and reversion of the transformed phenotype. These results show that elevation of intracellular cAMP levels abrogates the p21(ras) MAP kinase pathway at a step downstream of p21(ras) activation. This finding provides a molecular basis for the growth-inhibitory action of cAMP in normal and transformed fibroblasts.