SOMATOSTATIN INHIBITS AP-1 FUNCTION VIA MULTIPLE PROTEIN PHOSPHATASES

We have reported previously that the widespread inhibitory actions of somatostatin might be mediated by its ability to inhibit the expressio n of the immediate early genes c-fos and c-jun. The products of these genes form a heterodimeric transcription factor complex [activator pro tein 1 (AP-1)], which is known to be induced by treatment with phorbol esters. In the present study, we sought to investigate the mechanisms by which somatostatin inhibits immediate early gene expression. For o ur experiments, we used a rat pituitary adenoma cell line (GH(3)), whi ch is known to express multiple subclasses of somatostatin receptors. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulate d both AP-1 binding and transcriptional activity in GH(3) cells and th e somatostatin analogue octreotide inhibited this response by 40-70%. In the presence of two different phosphatase inhibitors, sodium orthov anadate or okadaic acid, the ability of somatostatin to inhibit AP-1 b inding and transcriptional activity was abolished. This effect of octr eotide, which appears to be mediated by the SSTR(2) and SSTR(5) subtyp es of somatostatin receptors, was paralleled by its ability to inhibit TPA-stimulated GH(3) cell proliferation. Pretreatment of the GH(3) ce lls with pertussis toxin (200 ng/ml) reversed the inhibitory effect of octreotide on both AP-1 function and cellular proliferation. Our obse rvations lead us to conclude that somatostatin not only inhibits immed iate early gene expression but also inhibits AP-1 binding and transcri ptional activity via the action of several classes of protein phosphat ases. This effect, which is pertussis toxin sensitive, might be one me chanism by which somatostatin inhibits cellular proliferation.