Brewer J W, Diehl J A
Department of Microbiology and Immunology, Loyola University Medical Center, Omaha, NE 68198-6805, USA.
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12625-30. doi: 10.1073/pnas.220247197.
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 (Ire1alpha, Ire1beta, and PERK) have been implicated as proximal effectors 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 2alpha (eIF2alpha), 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.
内质网（ER）中未折叠蛋白的积累会触发未折叠蛋白反应（UPR）信号通路。UPR在细胞周期的G1期协调内质网伴侣蛋白的诱导与蛋白质合成减少及生长停滞。三种内质网跨膜蛋白激酶（Ire1α、Ire1β和PERK）被认为是哺乳动物UPR的近端效应器。我们现在证明，PERK的激活标志着UPR过程中细胞周期蛋白D1的缺失，最终导致细胞周期停滞。在没有内质网应激的情况下，野生型PERK的过表达抑制了细胞周期蛋白D1的合成，从而诱导G1期停滞。PERK的表达与翻译延伸起始因子2α（eIF2α）磷酸化增加有关，这一事件先前已被证明会阻断细胞周期蛋白D1的翻译。相反，一种缺失激酶结构域的截短形式的PERK在细胞中过表达时作为显性负性因子起作用，在不影响内质网伴侣蛋白诱导的情况下，减弱UPR过程中细胞周期蛋白D1的缺失和细胞周期停滞。这些数据表明，PERK是UPR诱导的生长停滞的关键效应器，将内质网应激与细胞周期进程的控制联系起来。
