Data from Adaptive Basal Phosphorylation of eIF2α Is Responsible for Resistance to Cellular Stress–Induced Cell Death in <i>Pten</i>-Null Hepatocytes

Abstract

<div>Abstract<p>The α-subunit of eukaryotic initiation factor 2 (eIF2α) is a key translation regulator that plays an important role in cellular stress responses. In the present study, we investigated how eIF2α phosphorylation can be regulated by a tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) and how such regulation is used by PTEN-deficient hepatocytes to adapt and cope with oxidative stress. We found that eIF2α was hyperphosphorylated when <i>Pten</i> was deleted, and this process was AKT dependent. Consistent with this finding, we found that the <i>Pten</i>-null cells developed resistance to oxidative glutamate and H<sub>2</sub>O<sub>2</sub>-induced cellular toxicity. We showed that the messenger level of CReP (constitutive repressor of eIF2α phosphorylation), a constitutive phosphatase of eIF2α, was downregulated in <i>Pten</i>-null hepatocytes, providing a possible mechanism through which PTEN/AKT pathway regulates eIF2α phosphorylation. Ectopic expression of CReP restored the sensitivity of the <i>Pten</i> mutant hepatocytes to oxidative stress, confirming the functional significance of the downregulated CReP and upregulated phospho-eIF2α in the resistance of <i>Pten</i> mutant hepatocytes to cellular stress. In summary, our study suggested a novel role of PTEN in regulating stress response through modulating the CReP/eIF2α pathway. <i>Mol Cancer Res; 9(12); 1708–17. ©2011 AACR</i>.</p></div>