Translational Control of Prostaglandin Synthase by Growth Factors and Glucocorticoids
The discovery that both glucocorticoids and non-steroidal anti-inflammatory drugs such as aspirin inhibit synthesis of prostaglandins represented a major advance in our understanding of inflammatory processes. Whereas the non-steroidal drugs inhibit the enzyme prostaglandin synthase directly, the molecular basis for the action of the glucocorticoids is incompletely understood. Glucocorticoids have been shown to inhibit prostaglandin production both by inhibiting release of arachidonic acid substrate and by suppressing PG synthase levels directly. In cells with a high degree of glucocorticoid sensitivity, the latter effect predominates.
The principal mechanism in glucocorticoid-treated cells studied in tissue culture is a new type of translational control of the messenger RNA for the PG synthase enzyme. In common with other examples of translational control recently characterized this may involve interaction of glucocorticoid-induced or glucocorticoid activated proteins with a highly conserved 3′ UTR in the PG synthase mRNA, converting the mRNA into a nontranslated cryptic form. The glucocorticoid-linked lipocortin/annexin family of proteins appear to be involved in this process. In sensitive cells, translation of the cryptic form of PG synthase mRNA is activated by EGF. This is accompanied by phosphorylation of endogenous lipocortin by the protein kinase activity of the EGF receptor. The possibility that glucocorticoids induce specific protein phosphatases as suggested by Zor elsewhere in this volume needs further exploration.
A second mechanism by which glucocorticoids suppress prostaglandin synthesis is to inhibit release of arachidonic acid substrate by phospholipase A2. The long-held belief that this is due to a direct inhibitory action of lipocortin on PLA2 has recently been disproved. Instead glucocorticoids inhibit PLA2 in some cells directly by inducing dephosphorylation of the active form of the enzyme. In vascular smooth muscle cells, glucocorticoids inhibit expression of the phospholipase A2 enzyme both at the transcriptional and translational levels by mechanisms that remain to be determined.
These recent findings are important since they indicate that translational control of PG synthase by glucocorticoids may be representative of a more general phenomenon, and may provide a new role for the ubiquitous lipocortin annexin family of proteins. The further implication that growth factors and glucocorticoids differentially influence the phosphorylation status of the annexins could have important consequences for understanding the role of these compounds in cellular homeostasis.
KeywordsEpidermal Growth Factor Receptor Epidermal Growth Factor Creatine Kinase Vascular Smooth Muscle Cell Prostaglandin Synthesis
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