Molecular basis for somatostatin action: inhibition of c-fos expression and AP-1 binding.
Molecular basis for somatostatin action: inhibition of c-fos expression and AP-1 binding.
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生长抑素作用的分子基础：抑制 c-fos 表达和 AP-1 结合。
DOI：
10.1152/ajpgi.1994.267.2.g245
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Yamada,T
中科院分区：
文献类型：
--
作者：
Todisco,A;Campbell,V;Dickinson,CJ;DelValle,J;Yamada,T
生长抑素发挥其广泛的抑制作用的机制已被广泛研究，但只了解部分。最近的研究表明，生长抑素可以直接抑制基因转录。鉴于早期反应基因在诱导基因表达中的重要性，我们研究了生长抑素的作用是否可能通过抑制早期反应基因来介导。已知这些基因中的一些的产物，例如c-fos和c-jun，形成特异性结合共有序列TGAC（G）TCA的异二聚体转录因子复合物（AP-1）。因此，我们研究了生长抑素对c-fos基因表达和AP-1复合物与其特异性DNA元件结合的影响，使用分离的胃壁细胞和GH 3垂体细胞系。在壁细胞和GH 3细胞中，c-fos特异性mRNA被已知通过腺苷-3 '，5'-环磷酸和Ca（2+）依赖性信号机制起作用的药物增加，奥曲肽显著抑制这种反应。百日咳毒素预处理（200 ng/ml）可逆转奥曲肽的抑制作用。用32 P标记的AP-1寡核苷酸探针通过凝胶位移测定法评估AP-1结合活性，其被二丁酰腺苷3 '，5'-环一磷酸和血清刺激，并被奥曲肽处理抑制。我们的观察结果支持的概念，即生长抑素的普遍抑制作用可能是通过百日咳毒素敏感的抑制途径抑制早期反应基因的表达介导的。这种效应似乎导致调节核蛋白与其特异性DNA元件的结合减少，从而可能导致基因表达减少。
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.