Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice

Nair, Sreejayan; Xu, Changjiang; Shen, Guoxiang; Hebbar, Vidya; Gopalakrishnan, Avantika; Hu, Rong; Jain, Mohit Raja; Liew, Celine Valeria; Chan, Julia Y.; Kong, Ah‐Ng Tony

doi:10.1016/j.toxlet.2006.10.012

Cited by 56 publications

(45 citation statements)

References 40 publications

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“…Many phase II detoxifying genes, including glutathione S-transferase (GST) isoforms and GCLM, were found to be downregulated in an Nrf2-dependent manner (Nair et al 2007). Combined with the results from our study, it is likely that the observed down-regulation of the Nrf2-mediated response in the early study was due to the upregulation of Hrd1 by tunicamycin.…”

Section: Discussionsupporting

confidence: 65%

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

et al. 2014

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Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Downregulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.

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Section: Discussionsupporting

confidence: 65%

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

et al. 2014

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“…The only change in gene expression that was similar to what is seen in the UPR was a 2.4-fold increase in HERPUD1 in the adult series. No other changes in expression of genes known to be altered during the UPR or that appear in previous high density oligonucleotide array analyses of the UPR (15)(16)(17)(18)(19)(20) reached significance in this study, including absence of the 2.5-3-fold increase in GRP78 and GRP94 and 3.1-3.9-fold increase in protein-disulfide isomerase and its related proteins.…”

Section: Gene Expression Profile In the Liver In Response To Accumulacontrasting

confidence: 60%

Regulator of G Signaling 16 Is a Marker for the Distinct Endoplasmic Reticulum Stress State Associated with Aggregated Mutant α1-Antitrypsin Z in the Classical Form of α1-Antitrypsin Deficiency

Hidvegi

Mirnics

Hale

et al. 2007

Journal of Biological Chemistry

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In the classical form of ␣ 1 -antitrypsin deficiency, a mutant protein accumulates in a polymerized form in the endoplasmic reticulum (ER) of liver cells causing liver damage and carcinogenesis by a gain-of-toxic function mechanism. Recent studies have indicated that the accumulation of mutant ␣ 1 -antitrypsin Z in the ER specifically activates the autophagic response but not the unfolded protein response and that autophagy plays a critical role in disposal of insoluble ␣ 1 -antitrypsin Z. In this study, we used genomic analysis of the liver in a novel transgenic mouse model with inducible expression to screen for changes in gene expression that would potentially define how the liver responds to accumulation of this mutant protein. There was no unfolded protein response. Of several distinct gene expression profiles, marked up-regulation of regulator of G signaling (RGS16) was particularly notable. RGS16 did not increase when model systems were exposed to classical inducers of ER stress, including tunicamycin and calcium ionophore, or when a nonpolymerogenic ␣ 1 -antitrypsin mutant accumulated in the ER. RGS16 was up-regulated in livers from patients with ␣ 1 -antitrypsin deficiency, and the degree of up-regulation correlated with the hepatic levels of insoluble ␣ 1 -antitrypsin Z protein. Taken together, these results indicate that expression of RGS16 is an excellent marker for the distinct form of "ER stress" that occurs in ␣ 1 -antitrypsin deficiency, presumably determined by the aggregation-prone properties of the mutant protein that characterizes the deficiency.The histological hallmark of the classical form of ␣ 1 -antitrypsin (AT) 2 deficiency is liver cells containing periodic acidSchiffϩ/diastase-resistant globules. From many years of research on the disease, we now know that these globules represent rough endoplasmic reticulum (ER) distended by accumulation of the mutant ATZ molecule (where ATZ is the Z variant of ␣ 1 -antitrypsin). The wild type AT is a classical liverderived secretory glycoprotein that is delivered by the circulating blood to tissues to subserve its predominant function of inhibiting the neutrophil serine proteases neutrophil elastase, cathepsin G, and proteinase 3. The point mutation that characterizes the ATZ variant converts glutamate 342 to lysine and is sufficient to result in selective retention of the glycoprotein in the ER (reviewed in Refs. 1, 2). Thus, AT deficiency could be considered a prototype, naturally occurring "ER stress" state. Characterization of the structure of AT and its functional correlates led to the remarkable observation that the substitution of lysine for glutamate 342 conferred on the ATZ molecule a tendency to polymerize and aggregate (3, 4). Although it is still not clear whether the tendency to polymerize is the cause, or an effect, of ER retention, there is clear-cut evidence that polymers and aggregates of this molecule are formed in the ER, and there is growing evidence that these polymers and aggregates play a role in how liver cells respond and wh...

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“…ER stress was induced using palmitate or tunicamycin as described previously (34). Palmitate induces ER stress through degradation of carboxypeptidase E (35), whereas tunicamycin, an inhibitor of N-linked glycosylation, inhibits dolichol pyrophosphate-mediated glycosylation of asparaginyl residues of glycoproteins (36). Because glucose concentration affects ER stress in ␤ cells (37), we performed these studies under low and high glucose conditions.…”

Section: Er Stressmentioning

confidence: 99%

Differential Regulation of Endoplasmic Reticulum Stress by Protein Tyrosine Phosphatase 1B and T Cell Protein Tyrosine Phosphatase

Bettaieb

Liu

et al. 2011

Journal of Biological Chemistry

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Protein-tyrosine phosphatase 1B (PTP1B) and T cell proteintyrosine phosphatase (TCPTP) are closely related intracellular phosphatases implicated in the control of glucose homeostasis. PTP1B and TCPTP can function coordinately to regulate protein tyrosine kinase signaling, and PTP1B has been implicated previously in the regulation of endoplasmic reticulum (ER) stress. In this study, we assessed the roles of PTP1B and TCPTP in regulating ER stress in the endocrine pancreas. PTP1B and TCPTP expression was determined in pancreases from chow and high fat fed mice and the impact of PTP1B and TCPTP overor underexpression on palmitate-or tunicamycin-induced ER stress signaling assessed in MIN6 insulinoma ␤ cells. PTP1B expression was increased, and TCPTP expression decreased in pancreases of mice fed a high fat diet, as well as in MIN6 cells treated with palmitate. PTP1B overexpression or TCPTP knockdown in MIN6 cells mitigated palmitate-or tunicamycininduced PERK/eIF2␣ ER stress signaling, whereas PTP1B deficiency enhanced ER stress. Moreover, PTP1B deficiency increased ER stress-induced cell death, whereas TCPTP deficiency protected MIN6 cells from ER stress-induced death. ER stress coincided with the inhibition of Src family kinases (SFKs), which was exacerbated by PTP1B overexpression and largely prevented by TCPTP knockdown. Pharmacological inhibition of SFKs ameliorated the protective effect of TCPTP deficiency on ER stress-induced cell death. These results demonstrate that PTP1B and TCPTP play nonredundant roles in modulating ER stress in pancreatic ␤ cells and suggest that changes in PTP1B and TCPTP expression may serve as an adaptive response for the mitigation of chronic ER stress.

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Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice

Cited by 56 publications

References 40 publications

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

Regulator of G Signaling 16 Is a Marker for the Distinct Endoplasmic Reticulum Stress State Associated with Aggregated Mutant α1-Antitrypsin Z in the Classical Form of α1-Antitrypsin Deficiency

Differential Regulation of Endoplasmic Reticulum Stress by Protein Tyrosine Phosphatase 1B and T Cell Protein Tyrosine Phosphatase

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