Somatostatin inhibits ap-1 function via multiple protein
phosphatases.
Todisco, Andrea, Catherine Seva, Yoshiaki Takeuchi, Chris J.
Dickinson, Tadataka Yamada.
Departments of Internal Medicine, Pediatrics and Physiology,
University of Michigan Medical Center, Ann Arbor, MI
APStracts 2:0043G, 1995.
We have reported previously that the widespread inhibitory actions of
somatostatin might be mediated by its ability to inhibit the
expression of the immediate early genes c-fos and c-jun. The products
of these genes form a heterodimeric transcription factor complex (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 our
experiments we used a rat pituitary adenoma cell line (GH3) which is
known to express multiple subclasses of somatostatin receptors. The
phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulated
both AP-1 binding and transcriptional activity in GH3 cells and the
somatostatin analogue octreotide inhibited this response by 40-70%.
In the presence of two different phosphatase inhibitors, sodium
orthovanadate or okadaic acid, the ability of somatostatin to inhibit
AP-1 binding and transcriptional activity was abolished. This effect
of octreotide, which appears to be mediated by the SSTR2 and SSTR5
subtypes of somatostatin receptors, was paralleled by its ability to
inhibit TPA stimulated GH3 cell proliferation. Pretreatment of the
GH3 cells with pertussis toxin (200ng/ml) reversed the inhibitory
effect of octreotide on both AP-1 function and cellular
proliferation. Our observations lead us to conclude that somatostatin
not only inhibits immediate early gene expression but also inhibits
AP-1 binding and transcriptional activity via the action of several
classes of protein phosphatases. This effect, which is pertussis
toxin-sensitive, might be one mechanism by which somatostatin
inhibits cellular proliferation.
Received 12 September 1994; accepted in final form 21 February
1995.
APS Manuscript Number G349-4.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 21 March 1995.