THE CELLULAR PROTOONCOGENES C-FOS AND EGR-1 ARE REGULATED BY PROSTACYCLIN IN RODENT OSTEOBLASTS AND FIBROBLASTS

PGs are local regulators of various cellular functions. They exert the ir effects via specific PG receptor subtypes. Induction of c-fos gene expression has been described for arachidonic acid and its metabolite PGE(2). We demonstrate that another very short half-lifed prostanoid m etabolite, namely prostacyclin (PGI(2)), is a regulator of immediate-e arly genes. PGI(2) transiently induced the growth-associated immediate -early genes c-fos and egr-1 in osteoblastic as well as fibroblastic c ell lines. Furthermore, we showed that PGI(2) dose dependently stimula ted new DNA synthesis in the osteoblastic cell line MC3T3-E1. Although PGI(2) is known to be a potent inducer of cyclooxygenases, we showed that this pathway is not necessary for protooncogene induction by PGI( 2). Our data indicate a direct effect of PGI(2) on immediate-early gen e expression, which does not depend on the synthesis of other prostano ids. Intracellular signal transduction mechanisms were studied with th e protein kinase inhibitor H-7, a potent inhibitor of PGI(2)-induced c -fos expression. Experiments with phorbol esters revealed that protein kinase C activity is not obligatory for the effect of PGI(2) on c-fos expression. We conclude from these results that PGI(2), a rapidly ina ctivated prostanoid, has a major impact on cellular oncogene expressio n and growth in mesenchymally derived cells.