Amyloid precursor protein (APP) affects global protein synthesis in dividing human cells.
Amyloid precursor protein (APP) affects global protein synthesis in dividing human cells.
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DOI：
10.1002/jcp.24835
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发表时间：
2015-05
影响因子：
5.6
通讯作者：
Bocchetta, Maurizio
中科院分区：
文献类型：
--
作者：
Sobol, Anna;Galluzzo, Paola;Liang, Shuang;Rambo, Brittany;Skucha, Sylvia;Weber, Megan J.;Alani, Sara;Bocchetta, Maurizio
低分化非小细胞肺癌（NSCLC）依赖于Notch-1信号传导来生存。通过γ-分泌酶抑制剂（GSI）靶向Notch-1被证明可有效杀死缺氧NSCLC。GSI处理的NSCLC负荷小鼠的尸检分析表明，缺氧肿瘤组织中苏氨酸37/46处的4 E-BP 1磷酸化增强。对这种现象的体外解剖表明，淀粉样前体蛋白（APP）抑制是导致非经典4 E-BP 1磷酸化模式恢复的原因-这一过程部分由APP对假磷酸酶Styx的调节介导。APP耗竭后，我们观察到eIF-4F组成的改变，表明eIF-4A向mRNA帽的募集增加。这一现象得到了以下观察结果的支持，即APP耗尽的细胞对silvestrol（一种干扰eIF-4A组装成eIF-4F复合物的抗生素）具有部分抗性。在分裂的人类细胞中，APP下调增加了整体蛋白质合成的速率，这两者都依赖于cap和IRES。这种增加似乎与mTOR抑制无关。在给予Torin-1后，APP下调和雷帕霉素复合物1（mTORC-1）的机制靶点抑制以相反的方式影响4 E-BP 1磷酸化和整体蛋白质合成。其他研究表明，APP独立于mTORC-1运行。本研究中描述的关键现象通过APP C末端结构域的过表达而逆转。目前的数据表明，APP可能是一种新的调节蛋白质合成的分裂人类细胞，癌细胞和原发性。此外，APP似乎使用与mTORC-1调节帽依赖性蛋白质合成似乎不同的机制来影响翻译起始。J.细胞。230：1064-1074，2015。© 2014作者。细胞生理学杂志由Wiley Periodicals，Inc.出版。
Hypoxic non‐small cell lung cancer (NSCLC) is dependent on Notch‐1 signaling for survival. Targeting Notch‐1 by means of γ‐secretase inhibitors (GSI) proved effective in killing hypoxic NSCLC. Post‐mortem analysis of GSI‐treated, NSCLC‐burdened mice suggested enhanced phosphorylation of 4E‐BP1 at threonines 37/46 in hypoxic tumor tissues. In vitro dissection of this phenomenon revealed that Amyloid Precursor Protein (APP) inhibition was responsible for a non‐canonical 4E‐BP1 phosphorylation pattern rearrangement—a process, in part, mediated by APP regulation of the pseudophosphatase Styx. Upon APP depletion we observed modifications of eIF‐4F composition indicating increased recruitment of eIF‐4A to the mRNA cap. This phenomenon was supported by the observation that cells with depleted APP were partially resistant to silvestrol, an antibiotic that interferes with eIF‐4A assembly into eIF‐4F complexes. APP downregulation in dividing human cells increased the rate of global protein synthesis, both cap‐ and IRES‐dependent. Such an increase seemed independent of mTOR inhibition. After administration of Torin‐1, APP downregulation and Mechanistic Target of Rapamycin Complex 1 (mTORC‐1) inhibition affected 4E‐BP1 phosphorylation and global protein synthesis in opposite fashions. Additional investigations indicated that APP operates independently of mTORC‐1. Key phenomena described in this study were reversed by overexpression of the APP C‐terminal domain. The presented data suggest that APP may be a novel regulator of protein synthesis in dividing human cells, both cancerous and primary. Furthermore, APP appears to affect translation initiation using mechanisms seemingly dissimilar to mTORC‐1 regulation of cap‐dependent protein synthesis. J. Cell. Physiol. 230: 1064–1074, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
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