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Prostaglandin E₂-Induced Up-Regulation of c-fos Messenger Ribonucleic Acid Is Primarily Mediated by 3',5'-Cyclic Adenosine Monophosphate in MC3T3-E₁ Osteoblasts¹

From the Laboratory of Cell Growth, University of California, Department of Medicine and Department of Medicine, Veterans Affairs Medical Center, San Francisco, California 94121

Address all correspondence and requests for reprints to: Millie Hughes-Fulford, Laboratory of Cell Growth, University of California, Department of Medicine and Department of Medicine, Veterans Affairs Medical Center, Mail Code 151F, 4150 Clement Street, San Francisco, California 94121. E-mail: milliehf{at}aol.com

The mechanism by which the proto-oncogene, c-fos, is up-regulated in response to PGE₂ in the mouse osteoblastic (MC3T3-E₁) cell line was investigated using RT-PCR. c-fos messenger RNA up-regulation by dmPGE₂ is rapid, starting 10 min post stimulation, and transient. The specific protein kinase A (PKA) inhibitor, H89, inhibited c-fos induction. Moreover, down-regulation of protein kinase C (PKC) activity by chronic TPA treatment had no effect on the induction of c-fos by dmPGE₂. We conclude that up-regulation of c-fos by dmPGE₂ is primarily dependent on PKA in MC3T3-E₁ osteoblasts. In S49 lymphoma wild-type but not S49 cyc^- cells, which are deficient in cAMP signaling, dmPGE₂ up-regulates c-fos and increases cell growth compared with unstimulated cells. Thus in S49 lymphoma cells, c-fos induction by PGE₂ is also dependent on cAMP signaling. The minimal c-fos promoter region required for dmPGE₂-induced expression was identified by transfecting c-fos promoter deletion constructs coupled to the chloramphenicol acetyltransferase (CAT) reporter gene into Vero cells. Transfection of a plasmid containing 99 bp c-fos proximal promoter was sufficient to direct c-fos/CAT expression following stimulation with dmPGE₂. Because induction of c-fos is mediated by cAMP, these data are consistent with activation of c-fos via the CRE/ATF cis element.