Tumor suppression by PTEN requires the activation of the PKR-eIF2alpha phosphorylation pathway.
Inhibition of protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) at Ser(51) occurs as a result of the activation of a family of kinases in response to various forms of stress. Although some consequences of eIF2alpha phosphorylation are cytoprotective, phosphorylation of eIF2alpha by ... RNA-dependent protein kinase (PKR) is largely proapoptotic and tumor suppressing. Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is a tumor suppressor protein that is mutated or deleted in various human cancers, with functions that are mediated through phosphatase-dependent and -independent pathways. Here, we demonstrate that the eIF2alpha phosphorylation pathway is downstream of PTEN. Inactivation of PTEN in human melanoma cells reduced eIF2alpha phosphorylation, whereas reconstitution of PTEN-null human glioblastoma or prostate cancer cells with either wild-type PTEN or phosphatase-defective mutants of PTEN induced PKR activity and eIF2alpha phosphorylation. The antiproliferative and proapoptotic effects of PTEN were compromised in mouse embryonic fibroblasts that lacked PKR or contained a phosphorylation-defective variant of eIF2alpha. Induction of the pathway leading to phosphorylation of eIF2alpha required an intact PDZ-binding motif in PTEN. These findings establish a link between tumor suppression by PTEN and inhibition of protein synthesis that is independent of PTEN's effects on phosphoinositide 3'-kinase signaling.
Mesh Terms:
Analysis of Variance, Animals, Blotting, Western, Cell Line, Tumor, Colony-Forming Units Assay, Eukaryotic Initiation Factor-2, Fluorescent Antibody Technique, Humans, Immunoprecipitation, Mice, Microscopy, Confocal, PTEN Phosphohydrolase, Phosphorylation, Protein Synthesis Inhibitors, RNA Interference, Signal Transduction, Tumor Suppressor Proteins, eIF-2 Kinase
Analysis of Variance, Animals, Blotting, Western, Cell Line, Tumor, Colony-Forming Units Assay, Eukaryotic Initiation Factor-2, Fluorescent Antibody Technique, Humans, Immunoprecipitation, Mice, Microscopy, Confocal, PTEN Phosphohydrolase, Phosphorylation, Protein Synthesis Inhibitors, RNA Interference, Signal Transduction, Tumor Suppressor Proteins, eIF-2 Kinase
Sci Signal
Date: Dec. 22, 2009
PubMed ID: 20029030
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