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A more recent version of this article appeared on December 1, 2005
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Submitted on April 1, 2005
Revised on September 6, 2005
Accepted on September 11, 2005
Phosphorylation and Cell Cycle Arrest following Activation of the Unfolded Protein Response Pathway
The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology University of Pennsylvania Cancer Center, Philadelphia, PA 19104
Monitoring Editor: Mark Solomon
Exposure of cells to ER stress leads to activation of PERK, eIF2
phosphorylation, repression of cyclin D1 translation and subsequent cell cycle arrest in G1 phase. However, whether PERK is solely responsible for regulating cyclin D1 accumulation following UPR activation has not been assessed. Herein we demonstrate that repression of cyclin D1 translation following UPR activation occurs independently of PERK, but remains dependent on eIF2 phosphorylation. Although phosphorylation of eIF2 in PERK-/- fibroblasts is attenuated in comparison to wild type fibroblasts, it is not eliminated. The residual eIF2 phosphorylation correlates with the kinetics of cyclin D1 loss, suggesting that another eIF2 kinase functions in the absence of PERK. In cells harboring targeted deletion of both PERK and GCN2, cyclin D1 loss is attenuated suggesting GCN2 functions as the redundant kinase. Consistent with these results, cyclin D1 translation is also stabilized in cells expressing a nonphosphorylatable allele of eIF2; in contrast repression of global protein translation still occurs in these cells highlighting a high degree of specificity in transcripts targeted for translation inhibition by phosphorylated eIF2. Our results demonstrate that PERK and GCN2 function to cooperatively regulate eIF2 phosphorylation and cyclin D1 translation following UPR activation.
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