PERK mediates cell-cycle exit during the mammalian unfolded protein response

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) tri ggers the unfolded protein response (UPR)-signaling pathway. The UPR coordi nates the induction of ER chaperones with decreased protein synthesis and g rowth arrest in the G(1) phase of the cell cycle. Three ER transmembrane pr otein kinases (Ire1 alpha, Ire1 beta, and PERK) have been implicated as pro ximal effecters of the mammalian UPR. We now demonstrate that activation of PERK signals the loss of cyclin D1 during the UPR, culminating in cell-cyc le arrest. Overexpression of wild-type PERK inhibited cyclin D1 synthesis i n the absence of ER stress, thereby inducing a G(1) phase arrest. PERK expr ession was associated with increased phosphorylation of the translation elo ngation initiation factor 2 alpha (elF2 alpha), an event previously shown t o 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 with out compromising induction of ER chaperones. These data demonstrate that PE RK serves as a critical effector of UPR-induced growth arrest, linking stre ss in the ER to control of cell-cycle progression.