PERK-regulated protein translation mediates cell cycle arrest and survival during the Unfolded Protein Response.

Proper response to cellular insults is critical for maintenance of cellular function and viability. The endoplasmic reticulum (ER) is the cellular organelle that coordinates the translation, glycosylation, and folding of secreted and integral membrane proteins and is thus sensitive to a myriad of cellular insults that impair proper production of ER-translated proteins. In response to stress sensed by the ER, a signaling cascade termed the Unfolded Protein Response (UPR) is initiated which coordinates regulation of cellular transcription and translation in an effort to regain cellular homeostasis. One of the proximal effectors of the UPR is the ER resident kinase PERK. Upon activation, PERK phosphorylates the eukaryotic translation initiation factor 2alpha, attenuating bulk cellular protein translation, while paradoxically upregulating the translation of specific stress-related mRNAs. Cells that lack the PERK-eIF2alpha arm of the UPR are acutely sensitive to stresses that cause ER disfunction. This work describes the eIF2alpha-dependent translational regulation of cyclin D1 and cellular inhibitor of apoptosis (cIAP) mRNAs. Proper regulation of cyclin D1 transcript results in cell cycle arrest in the G1 phase of the cell cycle, while ER stress-induced translation of cIAP mRNA contributes to cellular survival of stress.