PKA-CREB Signaling Suppresses Tau Transcription
PKA-CREB Signaling Suppresses Tau Transcription
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PKA-CREB 信号传导抑制 Tau 转录
DOI：
10.3233/jad-142610
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发表时间：
2015-01-01
影响因子：
4
通讯作者：
Qian, Wei
中科院分区：
文献类型：
--
作者：
Liu, Huanliang;Jin, Xiaoxia;Qian, Wei
在阿尔茨海默病（AD）患者的大脑中，累积的和异常过度磷酸化的tau聚集成神经元缠结。cAMP反应结合蛋白（CREB）是一种组成性表达的核转录因子，是神经保护性转录网络的重要组成部分。大量研究表明，cAMP依赖性蛋白激酶（PKA）-CREB信号在AD脑中下调。在本研究中，我们研究了PKA-CREB信号通路对tau蛋白表达的调控。我们发现人tau基因的启动子含有三个潜在的cAMP反应元件（CRE）样元件CRE 1、CRE 2和CRE 3。CREB的过表达或PKA的激活在mRNA和蛋白水平上显著抑制tau蛋白的表达。ChIP（Chromatin immunoprecipitation）和EMSA（electrophoretic mobility shift assay）结果表明，CREB与这3个CRE顺式元件相互作用，其中CRE 1在抑制tau蛋白表达中起着最重要的作用。此外，PKA-CREB信号转导的上调抑制内源性tau蛋白的表达。总的来说，这些结果表明，PKA-CREB信号转导下调tau蛋白的表达，减少tau蛋白的转录，这可能提供了一个新的见解tau蛋白的表达调控和参与AD的tau发病机制的分子机制。
Accumulated and abnormally hyperphosphorylated tau aggregates into neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). cAMP response binding protein (CREB), a constitutively expressed nuclear transcription factor, is a critical component of the neuroprotective transcriptional network. Numerous studies have shown that cAMP-dependent protein kinase (PKA)-CREB signaling is down-regulated in AD brain. In the present study, we studied the regulation of tau expression by PKA-CREB signaling. We found that the promoter of human tau gene contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2, and CRE3. Overexpression of CREB or activation of PKA significantly suppressed the expression of tau at mRNA and protein levels. ChIP (Chromatin immunoprecipitation) and EMSA (electrophoretic mobility shift assay) revealed that CREB interacted with these three CRE cis-element and that CRE1, among the three elements, plays the most important role in the suppression of tau expression. Furthermore, upregulation of PKA-CREB signaling suppressed expression of endogenous tau. Collectively, these results suggest that PKA-CREB signaling down-regulates tau expression by reducing tau transcription, which may provide a novel insight into the regulation of tau expression and a molecular mechanism involved in tau pathogenesis in AD.