Differential effect of covalent protein modification and glutathione depletion on the transcriptional response of Nrf2 and NF-κB
| Autor: | Alvin J. L. Chia, Paul Morgan, B. Kevin Park, Neil R. Kitteringham, Christopher E. Goldring, Shi Quan Wong |
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| Rok vydání: | 2010 |
| Předmět: |
Transcription
Genetic medicine.disease_cause environment and public health Biochemistry NF-κB Mice chemistry.chemical_compound 0302 clinical medicine GSH glutathione ARE anti-oxidant response element 0303 health sciences NF-kappa B respiratory system Glutathione 3. Good health Cell biology DILI drug-induced liver injury RNAi RNA interference Liver NAPQI N-acetyl-p-benzoquinineimine 030220 oncology & carcinogenesis NF-κB NF-kappa B CRMs chemically reactive metabolites Signal transduction medicine.drug Keap1 NAPQI NF-E2-Related Factor 2 Cellular stress DNCB dinitrochlorobenzene Biology digestive system Article Nrf2 Cell Line 03 medical and health sciences Transcriptional response medicine Animals BSO buthionine (S R)-sulfoximine 030304 developmental biology Pharmacology Proteins Nrf2 nuclear factor-erythroid 2 (NF-E2)-related factor NFKB1 KEAP1 chemistry RNAi Drug metabolism Oxidative stress Protein Modification Translational |
| Zdroj: | Biochemical Pharmacology |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2010.04.004 |
| Popis: | Graphical abstract CRMs activate Nrf2, but inhibit NF-κB, and GSH depletion without covalent modification activates both Nrf2 and NF-κB. This leads to cellular protection against the potentially harmful effects of redox perturbation. Liver injury associated with exposure to therapeutic agents that undergo hepatic metabolism can involve the formation of reactive metabolites. These may cause redox perturbation which can result in oxidative stress as well as protein modification leading to activation or inhibition of cellular transcriptional responses. Nevertheless, the effects of these challenges on more than one transcriptional pathway simultaneously remain unclear. We have investigated two transcription factors known to be sensitive to electrophilic stress and redox perturbation, Nrf2 and NF-κB, in mouse liver cells. Cellular stress was induced by the probes: N-acetyl-p-benzoquinineimine (NAPQI), the reactive metabolite of acetaminophen; dinitrochlorobenzene (DNCB), a model electrophile; and buthionine (S,R)-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase. NAPQI, DNCB and BSO can all cause glutathione (GSH) depletion; however only NAPQI and DNCB can covalently bind proteins. We also employed RNAi to manipulate Keap1 (the inhibitor of Nrf2), Nrf2 itself and NF-κB-p65, to understand their roles in the response to drug stress. All three chemicals induced Nrf2, but NF-κB binding activity was only increased after BSO treatment. In fact, NF-κB binding activity decreased after exposure to NAPQI and DNCB. While RNAi depletion of Keap1 led to reduced toxicity following exposure to DNCB, depletion of Nrf2 and NF-κB augmented toxicity. Interestingly, increased Nrf2 caused by Keap1 depletion was reversed by co-depletion of NF-κB. We demonstrate that Keap1/Nrf2 and NF-κB respond differently to electrophiles that bind proteins covalently and the redox perturbation associated with glutathione depletion, and that crosstalk may enable NF-κB to partly influence Nrf2 expression during cellular stress. |
| Databáze: | OpenAIRE |
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