title: Translational regulation of GPx-1 and GPx-4 by the mTOR pathway.
abstract: Glutathione peroxidase activity was previously determined to be elevated in lymphocytes obtained from patients treated with the Bcr-Abl kinase inhibitor imatinib mesylate. In order to expand upon this observation, the established chronic myelogenous leukemia cell lines KU812 and MEG-01 were treated with imatinib and the effect on several anti-oxidant proteins was determined. The levels of GPx-1 were significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of many different proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx-1 and GPx-4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating anti-oxidants of the selenoprotein family via the mTOR pathway.
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Emily N
authors.initials: EN
authors.lastname: Reinke
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Dede N
authors.initials: DN
authors.lastname: Ekoue
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Soumen
authors.initials: S
authors.lastname: Bera
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Nadim
authors.initials: N
authors.lastname: Mahmud
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Diamond
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016044:Fusion Proteins, bcr-abl; D005979:Glutathione Peroxidase; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D047428:Protein Kinase Inhibitors; D051140:Selenoproteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human