Modulation of c-jun and jun-B messenger RNA and inhibition of DNA synthesis by prostaglandin E2 in Syrian hamster embryo cells.

Fatty acid metabolites such as prostaglandins are important regulators of DNA synthesis and cell proliferation. However, the mechanisms involved in this regulation are unclear. We have examined the effects of several fatty acid metabolites on the expression of the growth-related genes c-jun and jun-B in Syrian hamster embryo cells. Treatment of cells with prostaglandin E2 (PGE2) resulted in the inhibition of epidermal growth factor (EGF)-induced DNA synthesis and c-jun mRNA accumulation, whereas PGE2 augmented EGF-stimulated jun-B mRNA and markedly stimulated jun-B accumulation in the absence of EGF. Treatment of cells with PGE2 resulted in rapid accumulation of cyclic AMP (cAMP), whereas prostaglandin F2 alpha did not stimulate cAMP formation and did not alter EGF-stimulated DNA synthesis or accumulation of c-jun or jun-B mRNA. Forskolin and 8-(4-chlorophenylthio)-cAMP mimicked the effects of PGE2 on DNA synthesis and on the expression of c-jun and jun-B, suggesting the involvement of cAMP. We have shown that EGF-induced DNA synthesis requires the formation of hydroxyoctadecadienoic acids, formed from linoleic acid by a 15-lipoxygenase, in Syrian hamster embryo cells (Glasgow et al., J. Biol. Chem., 267: 10771-10779). Inhibition of this 15-lipoxygenase blocked EGF-dependent hydroxyoctadecadienoic acid formation and mitogenesis but did not affect EGF-stimulated c-jun or jun-B mRNA accumulation. The data suggest that the modulation of EGF-dependent DNA synthesis by PGE2 is associated with altered expression of c-jun and jun-B in Syrian hamster embryo cells. In contrast, hydroxyoctadecadienoic acids appear to act downstream or divergent from c-jun and jun-B expression in the regulation of EGF-dependent DNA synthesis.