MOLECULAR-BASIS FOR SOMATOSTATIN ACTION - INHIBITION OF C-FOS EXPRESSION AND AP-1 BINDING

The mechanisms by which somatostatin exerts its widespread inhibitory actions have been investigated extensively but understood only partial ly. Recent studies have shown that somatostatin can inhibit gene trans cription directly. In view of the critical importance of early respons e genes in induction of gene expression, we examined whether the actio n of somatostatin might be mediated by inhibition of early response ge nes. The products of some of these genes, such as c-fos and c-jun, are known to form a heterodimeric transcription factor complex (AP-1) tha t binds specifically to the consensus sequence TGAC(G)TCA. Accordingly , we examined the effects of somatostatin on c-fos gene expression and on the binding of the AP-1 complex to its specific DNA element using isolated gastric parietal cells and the GH(3) pituitary cell line. In both parietal and GH(3) cells, c-fos-specific mRNA was increased by ag ents known to act via both adenosine 3',5'-cyclic monophosphate and Ca 2+-dependent signaling mechanisms, and octreotide significantly inhibi ted this response. Pertussis toxin pretreatment (200 ng/ml) reversed t he inhibitory effect of octreotide. AP-1 binding activity, assessed by gel shift assays using a P-32-labeled AP-1 oligonucleotide probe, was stimulated by dibutyryl adenosine 3',5'-cyclic monophosphate and seru m and inhibited by octreotide treatment. Our observations support the notion that the universal inhibitory action of somatostatin may be med iated by inhibition of expression of early response genes via a pertus sis toxin-sensitive inhibitory pathway. This effect appears to lead to decreased binding of regulatory nuclear proteins to their specific DN A elements resulting, presumably, in diminished gene expression.