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Vol. 16, Issue 12, 5493-5501, December 2005
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Phosphorylation and Cell Cycle Arrest after 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
Submitted April 1, 2005;
Revised September 6, 2005;
Accepted September 11, 2005
Monitoring Editor: Mark Solomon
Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of PKR-like ER kinase (PERK), eukaryotic translation initiation factor 2
(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 after unfolded protein response pathway (UPR) activation has not been assessed. Herein, we demonstrate that repression of cyclin D1 translation after UPR activation occurs independently of PERK, but it remains dependent on eIF2 phosphorylation. Although phosphorylation of eIF2 in PERK–/– fibroblasts is attenuated in comparison with 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 after UPR activation.
* These authors contributed equally to this work.
Address correspondence to: J. Alan Diehl (adiehl{at}mail.med.upenn.edu).
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