COMPLEX INTERACTIONS AMONG 2ND MESSENGER PATHWAYS, STEROID-HORMONES, AND PROTOONCOGENES OF THE FOS AND JUN FAMILIES CONVERGE IN THE REGULATION OF THE NERVE GROWTH-FACTOR GENE

Regulation of the expression of the nerve growth factor (NGF) gene has been reported previously to be mediated via the protooncogene c-fos. Activation of the protein kinase C pathway and 1,25-dihydroxyvitamin D 3 [1,25(OH)2D3] has also been reported to increase the pool of NGF tra nscripts in L929 fibroblasts. Here we show that activation of the cycl ic AMP second messenger pathway antagonized the effect of phorbol 12-m yristate 13-acetate (PMA) or serum on NGF synthesis, whereas it enhanc ed that of 1,25(OH)2D3. A positive effect was also observed when serum , PMA, and 1,25(OH)2D3 were added together, but dexamethasone reduced this enhancement. There was no close correlation between the increase in c-fos mRNA and that in NGF mRNA, suggesting that expression of the c-fos protooncogene is not necessarily followed by induction of the NG F gene. Rather, these two genes are simultaneously, and not sequential ly, induced after forskolin treatment. It appears that regulation of t he NGF gene depends on a repertoire of multiple regulatory AP-1 comple xes arising from activation of the second messenger pathways. This sug gests that NGF gene expression is under the control of a complex inter play among second messenger pathways, protooncogenes, and steroid horm ones such as 1,25(OH)2D3 and glucocorticoids.