Synergism between protein-kinase C and cAMP-dependent pathways in the expression of the interleukin-1 beta gene is mediated via the activator-protein-1 (AP-1) enhancer activity.
Synergism between protein-kinase C and cAMP-dependent pathways in the expression of the interleukin-1 beta gene is mediated via the activator-protein-1 (AP-1) enhancer activity.
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DOI：
10.1111/j.1432-1033.1993.tb17754.x
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发表时间：
1993-04
期刊：
影响因子：
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通讯作者：
E. Serkkola;Mikko Hurme
中科院分区：
文献类型：
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作者：
E. Serkkola;Mikko Hurme
在许多不同的细胞类型中，用佛波醇酯（例如4 β-佛波醇12-肉豆蔻酸酯13-乙酸酯，PMA）处理导致蛋白激酶C（PKC）的活化，随后导致活化剂蛋白-1（AP-1）响应性基因表达的活化。我们以前曾报道过cAMP的结构类似物（二丁酰cAMP，Bt 2cAMP）或提高内源性cAMP水平的药物强烈增强PMA诱导的人髓性白血病细胞（THP-1，HL-60）中白细胞介素-1 β（IL-1 β）基因的表达。我们现在已经研究了AP-1在THP-1细胞中通过PKC和cAMP调节IL-1 β基因表达中的作用。AP-1是由jun和fos基因家族的产物组成的复合物。我们的研究表明，Bt 2cAMP增强PMA诱导的c-fos和jun-B表达，但抑制c-jun表达。电泳迁移率改变实验表明，Bt 2 cAMP也增加PMA诱导的AP-1 DNA结合活性。通过用含有AP-1位点的报告构建体[Col-TREx 5/TK-CAT和IL-1 β-X-CAT，其含有IL-1 β基因的推定的12-O-十四酰基-佛波醇-13-乙酸酯（TPA）-响应元件]转染THP-1细胞，研究AP-1 DNA结合活性增加的功能作用。瞬时转染实验表明，Bt 2cAMP类似地增加PMA诱导的转录从这两个报告构建体。总之，这些结果表明cAMP增加PMA诱导的AP-1活性，然后导致IL-1 β表达增加。
In many different cell types treatment with phorbol esters (e.g. 4 beta-phorbol 12-myristate 13-acetate, PMA) leads to the activation of protein-kinase C (PKC) and subsequently to the activation of the activator-protein-1(AP-1)-responsive gene expression. We have previously reported that a structural analog of cAMP (dibutyryl cAMP, Bt2cAMP) or agents elevating the endogenous cAMP levels strongly enhanced the PMA-induced interleukin-1 beta(IL-1 beta)-gene expression in human myeloid leukemia cells (THP-1, HL-60). We have now examined the role of AP-1 in the regulation of the IL-1 beta gene expression by PKC and cAMP in THP-1 cells. AP-1 is a complex composed of products of the jun and fos gene families. Our studies show that Bt2cAMP enhances the PMA-induced c-fos and jun-B expression, but inhibits c-jun expression. Electrophoretic mobility-shift assay revealed that Bt2cAMP also increased the PMA-induced AP-1 DNA-binding activity. The functional role of the increased AP-1 DNA-binding activity was studied by transfecting THP-1 cells with reporter constructs containing AP-1 sites [Col-TREx5/TK-CAT and IL-1 beta-X-CAT, which contains the putative 12-O-tetradecanoyl-phorbol-13-acetate(TPA)-responsive element of the IL-1 beta gene]. Transient transfection assay demonstrated that Bt2cAMP similarly increased the PMA-induced transcription from both of these reporter constructs. Taken together, these results suggest that cAMP increases the PMA-induced AP-1 activity which then leads to increased IL-1 beta expression.