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.

Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling

“…Notably, mitochondrial complex IV (COX) deficiency is corrected by PGC1α activation 74 . Another recent in vitro study showed a translational regulation of GPX1 and GPX4 by the mTOR pathway 75 . However, as mentioned above, the mTOR pathway does not appear to be induced in respiratory uncoupled muscle 30 .…”

Glutathione Peroxidase-1 Suppresses the Unfolded Protein Response upon Cigarette Smoke Exposure

“…Currently the mechanism by which cigarette smoke regulates GPx-1 expression is not fully elucidated but considering our GPx-1 reintroduction data further analysis of GPx-1 regulation is critical. GPx-1 expression and activity have been reported to be regulated by Nrf2 [34], the transcription factor TFAP2C [35], CpG methylation of the GPx-1 promoter [35], Bcr-Abl/mTOR [36], selenium [37], estrogen [38], adenosine [39], Sec-insertion sequence (SECIS) factors [40], EGFR [41], and homocysteine [42]. Specifically, within the lung during smoke exposure, Singh et al show elevated GPx-1 expression in the lungs following one-month cigarette smoke exposure that was regulated by Nrf2 [34].…”

Selenoproteins and cardiovascular stress

“…Bioavailable Se is not the only mechanism by which selenoprotein expression and function are regulated in the heart. Selenoproteins are regulated through the NF-E2-related factor 2 (Nrf2), Hypoxia-inducible factor 1α (HIF-1α), and mammalian target of rapamycin (mTOR) signalling pathways as well (78)(79)(80). Nrf2 is a major antioxidant response transcription factor that binds antioxidant response elements (AREs) in promoters of GPX1 and Txnrd1 genes along with other non-selenoprotein antioxidant factors.…”

“…HIF-2α KO mice suffer from greater oxidative stress due to low levels of antioxidant enzymes including GPX1 (90). A relationship between mTOR and GPX1 was uncovered in leukaemia patients receiving imatinib when it was noted that GPX1 levels were increased in these patients (80). It was shown that the imatinib blocked Bcr-Abl signalling and in turn decreased mTOR signalling, which increased GPX1 and 4 activity.…”