Dual role of cAMP in the transcriptional regulation of multidrug resistance-associated protein 4 (MRP4) in pancreatic adenocarcinoma cell lines.
Dual role of cAMP in the transcriptional regulation of multidrug resistance-associated protein 4 (MRP4) in pancreatic adenocarcinoma cell lines.
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DOI：
10.1371/journal.pone.0120651
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fernández N
中科院分区：
文献类型：
--
作者：
Carozzo A;Diez F;Gomez N;Cabrera M;Shayo C;Davio C;Fernández N
环AMP是研究最多的信号分子之一，其在增殖和分化过程中的作用已经得到了很好的证实。细胞内cAMP水平受到严格调控，其中MRP4转运体起主要作用。在本研究中，我们试图确定cAMP是否调节了胰腺腺癌细胞系中MRP4的表达。定量PCR和western blot研究表明，camp增加剂增强了PANC-1细胞中MRP4转录物和蛋白水平。在胰腺AR42J细胞中进行的报告荧光素酶实验表明，细胞内cAMP通过Epac2和Rap1介导的机制上调MRP4，而细胞外cAMP通过MEK/ erk介导的途径降低MRP4启动子活性。目前的研究结果表明，cAMP调节MRP4启动子活性，并进一步表明细胞内和细胞外cAMP水平的平衡决定了MRP4的表达。
Cyclic AMP represents one of the most studied signaling molecules and its role in proliferation and differentiation processes has been well established. Intracellular cAMP levels are tightly regulated where the MRP4 transporter plays a major role. In the present study, we sought to establish whether cAMP modulated MRP4 expression in pancreatic adenocarcinoma cell lines. Quantitative PCR and western blot studies showed that cAMP-increasing agents enhanced MRP4 transcripts and protein levels in PANC-1 cells. Reporter luciferase experiments carried out in pancreatic AR42J cells showed that intracellular cAMP up-regulates MRP4 through an Epac2- and Rap1- mediated mechanism whereas extracellular cAMP reduced MRP4 promoter activity by a MEK/ERK-mediated pathway. Present results show that cAMP regulates MRP4 promoter activity, and further indicate that the balance between intracellular and extracellular cAMP levels determines MRP4 expression.
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