Adaptive basal phosphorylation of eIF2α is responsible for resistance to cellular stress-induced cell death in Pten-null hepatocytes.
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 Pten was deleted, and this process was AKT dependent. Consistent with this finding, we found that the Pten-null cells developed resistance to oxidative glutamate and H(2)O(2)-induced cellular toxicity. We showed that the messenger level of CReP (constitutive repressor of eIF2α phosphorylation), a constitutive phosphatase of eIF2α, was downregulated in Pten-null hepatocytes, providing a possible mechanism through which PTEN/AKT pathway regulates eIF2α phosphorylation. Ectopic expression of CReP restored the sensitivity of the Pten mutant hepatocytes to oxidative stress, confirming the functional significance of the downregulated CReP and upregulated phospho-eIF2α in the resistance of Pten 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.
Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, California 90089, USA.
Ni
N
Zeng
Yang
Y
Li
Lina
L
He
Xiaoling
X
Xu
Vivian
V
Galicia
Chuxia
C
Deng
Bangyan L
BL
Stiles
D000818:Animals; D016923:Cell Death / Q000235:genetics*; D002470:Cell Survival; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000737:chemistry; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000187:drug effects; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous
D002867:Chromones; D015852:Eukaryotic Initiation Factor-2; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; C480350:Ppp1r15b protein, mouse; D054645:Protein Phosphatase 1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse