期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1823, 期 6, 页码 1102-1109出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2012.04.002
关键词
Nrf2; Lipoic acid; Mammalian target of rapamycin (mTOR); Cap-independent translation; Protein homeostasis; Cellular stress
资金
- National Institutes of Health [R01 2AG17141, P01 AT002034-01]
- [T32 AT002688-01]
Little is known about either the basal or stimulated homeostatic mechanisms regulating nuclear tenure of Nf-e2-related factor 2 (Nrf2), a transcription factor that mediates expression of over 200 detoxification genes. Our data show that stress-induced nuclear Nrf2 accumulation is largely from de novo protein synthesis, rather than translocation from a pre-existing cytoplasmic pool. HepG2 cells were used to monitor nuclear Nrf2 24 h following treatment with the dithiol micronutrient (R)-alpha-lipoic acid (LA; 50 mu M), or vehicle. LA caused a >= 2.5-fold increase in nuclear Nrf2 within 1 h. However, pretreating cells with cycloheximide (50 mu g/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4 h, but LA overcame this inhibition. LA-mediated de novo protein translation was confirmed using HepG2 cells transfected with a bicistronic construct containing an internal ribosome entry sequence (IRES) for Nrf2, with significant (P<0.05) increase in IRES use under LA treatment. These results suggest that a dithiol stimulus mediates Nrf2 nuclear tenure via cap-independent protein translation. Thus, translational control of Nrf2 synthesis, rather than reliance solely on pre-existing protein, may mediate the rapid burst of Nrf2 nuclear accumulation following stress stimuli. (C) 2012 Published by Elsevier B.V.
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