Depletion of Amyloid Precursor Protein (APP) causes G0 arrest in non-small cell lung cancer (NSCLC) cells.
Depletion of Amyloid Precursor Protein (APP) causes G0 arrest in non-small cell lung cancer (NSCLC) cells.
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DOI：
10.1002/jcp.24875
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发表时间：
2015-06
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;Weber, Megan J.;Alani, Sara;Bocchetta, Maurizio
我们最近报道了淀粉样前体蛋白（APP）在包括非小细胞肺癌（NSCLC）细胞在内的多种人类分裂细胞中调节整体蛋白质合成。更具体地说，APP耗竭导致帽依赖性和IRES依赖性翻译的增加。由于生长和增殖是紧密耦合的过程，在这里，我们询问了APP的人工下调可能在NSCLC细胞增殖中引起的影响。APP耗竭导致G 0/G1期阻滞，通过不稳定的细胞周期蛋白-C蛋白和减少pRb磷酸化的残基Ser 802/811。细胞周期蛋白-C的siRNA反映了沉默APP时观察到的细胞周期分布。停滞在G 0/G1期（并且具有增强的全局蛋白质合成）的细胞增加了它们的大小，并且由于细胞膜透化而经历了坏死性细胞死亡。这些表型被逆转的APP C-末端结构域的过表达，表明APP在调节早期细胞周期进入决策的新作用。APP似乎在细胞清除G1中期的生长因子和营养素依赖性检查点之前调节蛋白质合成速率。我们的研究结果提出了这样的过程如何相互作用的背景下（至少）分裂的NSCLC细胞的问题。这里提供的数据表明，APP，虽然需要G 0/G1转换，缓和蛋白质合成速率之前，细胞完全致力于细胞周期进程的机制，这似乎是额外的并行信号来自PI 3-K/Akt/mTORC-1轴。APP似乎在调节蛋白质合成速率的细胞周期进入中起核心作用;其功能丧失导致细胞大小异常和死亡。
We recently reported that Amyloid Precursor Protein (APP) regulates global protein synthesis in a variety of human dividing cells, including non-small cell lung cancer (NSCLC) cells. More specifically, APP depletion causes an increase of both cap- and IRES-dependent translation. Since growth and proliferation are tightly coupled processes, here we asked what effects artificial downregulation of APP could have elicited in NSCLC cells proliferation. APP depletion caused a G0/G1 arrest through destabilization of the cyclin-C protein and reduced pRb phosphorylation at residues Ser802/811. siRNA to cyclin-C mirrored the cell cycle distribution observed when silencing APP. Cells arrested in G0/G1 (and with augmented global protein synthesis) increased their size and underwent a necrotic cell death due to cell membrane permeabilization. These phenotypes were reversed by overexpression of the APP C-terminal domain, indicating a novel role for APP in regulating early cell cycle entry decisions. It is seems that APP moderates the rate of protein synthesis before the cell clears growth factors- and nutrients-dependent checkpoint in mid G1. Our results raise questions on how such processes interact in the context of (at least) dividing NSCLC cells. The data presented here suggest that APP, although required for G0/G1 transitions, moderates the rate of protein synthesis before the cell fully commits to cell cycle progression following mechanisms, which seem additional to concurrent signals deriving from the PI3-K/Akt/mTORC-1 axis. APP appears to play a central role in regulating cell cycle entry with the rate of protein synthesis; and its loss-of-function causes cell size abnormalities and death.
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影响因子：
5.6
作者：
BAXTER, GC;STANNERS, CP
通讯作者：
STANNERS, CP
影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
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Bush AI
影响因子：
3.5
作者：
Palmer, Gregory M.;Fontanella, Andrew N.;Dewhirst, Mark W.
通讯作者：
Dewhirst, Mark W.
影响因子：
4.8
作者：
Nizzari, Mario;Venezia, Valentina;Russo, Claudio
通讯作者：
Russo, Claudio
影响因子：
4.8
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC