Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5'UTR and PI3K Signaling.
Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5'UTR and PI3K Signaling.
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DOI：
10.3389/fnmol.2018.00198
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发表时间：
2018
影响因子：
4.8
通讯作者：
Chen GJ
中科院分区：
文献类型：
--
作者：
Min Z;Tang Y;Hu XT;Zhu BL;Ma YL;Zha JS;Deng XJ;Yan Z;Chen GJ
α-分泌酶“一种含有崩解素和金属蛋白酶结构域的蛋白”（ADAM10）参与淀粉样前体蛋白（APP）的加工。上调ADAM10阻止了神经毒性β-淀粉样蛋白（a β）的产生，代表了阿尔茨海默病（AD）的一种合理的治疗策略。在这项研究中，我们探索了可能促进ADAM10表达的化合物。因此，我们在SH-SY5Y（人类神经母细胞瘤）细胞中进行了高通量小分子筛选，这些细胞稳定表达由ADAM10启动子驱动的荧光素酶报告基因，包括其5 ' -非翻译区（5 ' utr）的一部分。这导致了宇宙素（芹菜素7-O-β-葡萄糖苷）的发现。在这里，我们报道了在人类细胞系（SH-SY5Y和HEK293）中，宇宙素成比例地增加了未成熟和成熟形式的ADAM10蛋白的水平，而不改变其mRNA水平。翻译抑制剂或删除ADAM10的5'UTR会减弱这种作用，这表明翻译机制是ADAM10水平升高的原因。荧光素酶缺失实验显示，5'UTR的前144个核苷酸是介导宇宙素诱导的SH-SY5Y细胞ADAM10表达增强所必需的。Cosmosiin不能提高小鼠细胞中ADAM10蛋白的水平，因为小鼠细胞缺乏含有鉴定的5'UTR元件的ADAM10转录本的天然表达。潜在的信号通路可能涉及磷脂酰肌苷激酶3 (PI3K)，因为PI3K的药理抑制减弱了cosmosiin对ADAM10蛋白表达的影响。最后，由于宇宙素处理后HEK-APP细胞中Aβ40/42的水平显著降低，宇宙素降低了Aβ的生成。总的来说，我们发现ADAM10 5'UTR的前144个核苷酸和PI3K信号通路参与了宇宙素诱导的ADAM10蛋白表达增强。这些结果提示宇宙素可能是一种潜在的治疗阿尔茨海默病的药物。
The α-secretase “a disintegrin and metalloproteinase domain-containing protein” (ADAM10) is involved in the processing of amyloid precursor protein (APP). Upregulation of ADAM10 precludes the generation of neurotoxic β-amyloid protein (Aβ) and represents a plausible therapeutic strategy for Alzheimer’s disease (AD). In this study, we explored compounds that can potentially promote the expression of ADAM10. Therefore, we performed high-throughput small-molecule screening in SH-SY5Y (human neuroblastoma) cells that stably express a luciferase reporter gene driven by the ADAM10 promoter, including a portion of its 5’-untranslated region (5’UTR). This has led to the discovery of cosmosiin (apigenin 7-O-β-glucoside). Here, we report that in human cell lines (SH-SY5Y and HEK293), cosmosiin proportionally increased the levels of the immature and mature forms of the ADAM10 protein without altering its mRNA level. This effect was attenuated by translation inhibitors or by deleting the 5’UTR of ADAM10, suggesting that a translational mechanism was responsible for the increased levels of ADAM10. Luciferase deletion assays revealed that the first 144 nucleotides of the 5’UTR were necessary for mediating the cosmosiin-induced enhancement of ADAM10 expression in SH-SY5Y cells. Cosmosiin failed to increase the levels of the ADAM10 protein in murine cells, which lack native expression of the ADAM10 transcript containing the identified 5’UTR element. The potential signaling pathway may involve phosphatidylinositide 3-kinase (PI3K) because pharmacological inhibition of PI3K attenuated the effect of cosmosiin on the expression of the ADAM10 protein. Finally, cosmosiin attenuated Aβ generation because the levels of Aβ40/42 in HEK-APP cells were significantly reduced after cosmosiin treatment. Collectively, we found that the first 144 nucleotides of the ADAM10 5’UTR, and PI3K signaling, are involved in cosmosiin-induced enhancement of the expression of ADAM10 protein. These results suggest that cosmosiin may be a potential therapeutic agent in the treatment of AD.
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DOI：
10.1007/s00018-015-2111-z
发表时间：
2016-05
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
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影响因子：
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影响因子：
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作者：
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10.6
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影响因子：
16.2
作者：
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