PERK mediates cell-cycle exit during the mammalian unfolded protein response
PERK mediates cell-cycle exit during the mammalian unfolded protein response
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DOI：
10.1073/pnas.220247197
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发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Diehl, JA
中科院分区：
文献类型：
--
作者：
Brewer, JW;Diehl, JA
未折叠蛋白在内质网（ER）中的积累触发了未折叠蛋白反应（UPR）信号通路。UPR协调ER分子伴侣的诱导与细胞周期G（1）期蛋白质合成减少和生长停滞。三种ER跨膜蛋白激酶（Ire1 α、Ire1 β和PERK）被认为是哺乳动物UPR的近端效应物。我们现在证明，激活PERK信号周期蛋白D1的损失在UPR，最终在细胞周期停滞。野生型PERK的过表达抑制细胞周期蛋白D1的合成，在缺乏ER应激，从而诱导G（1）期阻滞。PERK表达与翻译延伸起始因子2 α（elF2 α）磷酸化增加有关，这是一种先前显示可阻断细胞周期蛋白D1翻译的事件。相反，一个截短形式的PERK缺乏其激酶结构域作为一个显性负时，在细胞中过表达，衰减细胞周期蛋白D1的损失和细胞周期停滞在UPR不损害诱导ER分子伴侣。这些数据表明，PERK作为一个关键效应的UPR诱导的生长停滞，连接在ER的压力，控制细胞周期的进展。
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR)-signaling pathway. The UPR coordinates the induction of ER chaperones with decreased protein synthesis and growth arrest in the G(1) phase of the cell cycle. Three ER transmembrane protein kinases (Ire1 alpha, Ire1 beta, and PERK) have been implicated as proximal effecters of the mammalian UPR. We now demonstrate that activation of PERK signals the loss of cyclin D1 during the UPR, culminating in cell-cycle arrest. Overexpression of wild-type PERK inhibited cyclin D1 synthesis in the absence of ER stress, thereby inducing a G(1) phase arrest. PERK expression was associated with increased phosphorylation of the translation elongation initiation factor 2 alpha (elF2 alpha), an event previously shown to block cyclin D1 translation. Conversely, a truncated form of PERK lacking its kinase domain acted as a dominant negative when overexpressed in cells, attenuating both cyclin D1 loss and cell-cycle arrest during the UPR without compromising induction of ER chaperones. These data demonstrate that PERK serves as a critical effector of UPR-induced growth arrest, linking stress in the ER to control of cell-cycle progression.