Molecular mechanisms for somatostatin inhibition of c-fos gene
expression.
Todisco, Andrea, Yoshiaki Takeuchi, Junko Yamada, Jun-Ichi Sadoshima,
Tadataka Yamada.
Departments of Internal Medicine and Physiology, University of
Michigan Medical Center, Ann Arbor, MI, USA
APStracts 3:0245G, 1996.
We reported previously that somatostatin inhibits the expression of
the immediate early gene c-fos. Accordingly, we characterized the
molecular mechanisms by which somatostatin inhibits c-fos gene
expression. Since growth factors activate c-fos through a region of
its promoter known as the SRE (bases -357 to -276) we transfected rat
pituitary adenoma cells (GH3) with plasmids containing the SRE or the
SRE core fragment (bases -320 to -298) upstream of the luciferase
reporter gene. EGF stimulated SRE-luciferase activity and this effect
was inhibited by somatostatin and by the analogue MK678. Identical
results were obtained with the SRE core- plasmid,demonstrating that
the sequence between bases -320 to -298 of the c-fos promoter is a
somatostatin response element. Since the ERKs induce the SRE via
phosphorylation of transcription factors such as Elk-1, we examined
the effect of somatostatin on ERKs phosphorylation and activation.
EGF stimulated tyrosine phosphorylation of ERK2 and MK678 attenuated
this effect. In experiments using in-gel kinase assays, MK678 also
inhibited EGF stimulated ERKs activity via a pertussis toxin
sensitive pathway and this effect resulted in inhibition of Elk-1
transcriptional activity. Our data suggest that one mechanism of
somatostatin action involves inhibition of ERKs activity, Elk-1
phosphorylation and transcriptional activation and, ultimately, c-fos
gene transcription.
Received 29 April 1996; accepted in final form 24 October 1996.
APS Manuscript Number G168-6.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996