Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription
Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription
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DOI：
10.1042/bj20040682
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发表时间：
2004-10-15
影响因子：
4.1
通讯作者：
Vivien, D
中科院分区：
文献类型：
--
作者：
Docagne, F;Gabriel, C;Vivien, D
A（淀粉样β肽）的异常沉积是AD（阿尔茨海默病）的标志之一。这种肽由其前体蛋白APP（淀粉样β前体蛋白）的加工和切割产生。我们先前已经证明，在AD患者中过度表达的TGF-β（转化生长因子-β）能够通过导致Abeta积累的转录机制增强星形胶质细胞的APP合成。在本研究中，我们旨在进一步表征维持这种TGF β依赖性转录活性的分子机制。我们报告了以下发现：首先，TGF-β能够诱导APP启动子+54/+74区域的报告基因构建体的转录活性，命名为App（TRE）（APP TGF-β-响应元件）;其次，尽管这种作用是由涉及Smad 3的转导途径介导的，Smad 4、Smad 2或其它Smads不能诱导App的活性（TRE）。我们还观察到，AppTRE序列不仅响应于Smad 3转录因子，而且Sp1（信号蛋白1）转录因子与Smads合作，以加强TGF-β依赖的APP激活。TGF-β信号转导诱导形成由Sp1，Smad 3和Smad 4组成的核复合物。总体而言，本研究提供了新的见解，更好地了解发生在转录水平和调节TGF-β依赖性转录的精细分子机制。在AD的背景下，我们的研究结果提供了额外的证据，TGF-β在调节Abeta生产的关键作用。
Abnormal deposition of A (amyloid-beta peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-beta precursor protein). We have demonstrated previously that TGF-beta (transforming growth factor-beta), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Abeta. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGFbeta-dependent transcriptional activity. We report the following findings: first, TGF-beta is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named App(TRE) (APP TGF-beta-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of App(TRE). We also observed that the AppTRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-beta-dependent activation of APP. TGF-beta signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-beta-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-beta in the regulation of Abeta production.