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 partially. Recent studies have shown that somatostatin can inhibit gene transcription directly. In view of the critical importance of early response genes in induction of gene expression, we examined whether the action of somatostatin might be mediated by inhibition of early response genes. 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) that 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 GH3 pituitary cell line. In both parietal and GH3 cells, c-fos-specific mRNA was increased by agents known to act via both adenosine-3',5'-cyclic monophosphate and Ca(2+)-dependent signaling mechanisms, and octreotide significantly inhibited this response. Pertussis toxin pretreatment (200 ng/ml) reversed the inhibitory effect of octreotide. AP-1 binding activity, assessed by gel shift assays using a 32P-labeled AP-1 oligonucleotide probe, was stimulated by dibutyryl adenosine 3',5'-cyclic monophosphate and serum and inhibited by octreotide treatment. Our observations support the notion that the universal inhibitory action of somatostatin may be mediated by inhibition of expression of early response genes via a pertussis toxin-sensitive inhibitory pathway. This effect appears to lead to decreased binding of regulatory nuclear proteins to their specific DNA elements resulting, presumably, in diminished gene expression.
Todisco
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A
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0368.
Campbell
V
V
Dickinson
C J
CJ
DelValle
J
J
Yamada
T
T
D000818:Animals; D001483:Base Sequence; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004285:Dogs; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D008969:Molecular Sequence Data; D015282:Octreotide / Q000494:pharmacology; D015345:Oligonucleotide Probes / Q000235:genetics; D010295:Parietal Cells, Gastric / Q000378:metabolism; D037342:Pertussis Toxin; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015345:Oligonucleotide Probes; D016755:Proto-Oncogene Proteins c-jun; D010566:Virulence Factors, Bordetella; D013004:Somatostatin; D006632:Histamine; D002217:Carbachol; D004247:DNA; D037342:Pertussis Toxin; D015282:Octreotide