scholarly journals Ischemia-like Oxygen and Glucose Deprivation Mediates Down-regulation of Cell Surface γ-Aminobutyric AcidBReceptors via the Endoplasmic Reticulum (ER) Stress-induced Transcription Factor CCAAT/Enhancer-binding Protein (C/EBP)-homologous Protein (CHOP)

2014 ◽  
Vol 289 (18) ◽  
pp. 12896-12907 ◽  
Author(s):  
Patrick J. Maier ◽  
Khaled Zemoura ◽  
Mario A. Acuña ◽  
Gonzalo E. Yévenes ◽  
Hanns Ulrich Zeilhofer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Cell Surface ◽  
Er Stress ◽  
Protein C ◽  
Glucose Deprivation ◽  
Down Regulation ◽  
Oxygen And Glucose Deprivation ◽  
Homologous Protein ◽  
Enhancer Binding Protein

scholarly journals Inhibition of Nuclear Factor-κB or Bax Prevents Endoplasmic Reticulum Stress- But Not Nitric Oxide-Mediated Apoptosis in INS-1E Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4094-4103 ◽  
Author(s):  
Morten F. Tonnesen ◽  
Lars G. Grunnet ◽  
Josefine Friberg ◽  
Alessandra K. Cardozo ◽  
Nils Billestrup ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Er Stress ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Β Cell ◽  
No Donor ◽  
Homologous Protein ◽  
Enhancer Binding Protein

Abstract Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca2+ depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) contributes to β-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca2+ depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor κB (NFκB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFκB activation, as assessed by IκB degradation and NFκB DNA binding. Inhibition of NFκB or the Bcl-2 family member Bax pathways protected β-cells against TG- but not SNAP-induced β-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFκB and Bax.

scholarly journals Inhibition of phosphatidylcholine synthesis induces expression of the endoplasmic reticulum stress and apoptosis-related protein CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153)

2003 ◽  
Vol 369 (3) ◽  
pp. 643-650 ◽  
Author(s):  
Michiel H.M. van der SANDEN ◽  
Martin HOUWELING ◽  
Lambert M.G. van GOLDE ◽  
Arie B. VAANDRAGER
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Binding Protein ◽  
Related Protein ◽  
Unfolded Proteins ◽  
Homologous Protein ◽  
Er Stress Response ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Inhibition of de novo synthesis of phosphatidylcholine (PC) by some anti-cancer drugs such as hexadecylphosphocholine leads to apoptosis in various cell lines. Likewise, in MT58, a mutant Chinese hamster ovary (CHO) cell line containing a thermo-sensitive mutation in CTP:phosphocholine cytidylyltransferase (CT), an important regulatory enzyme in the CDP-choline pathway, inhibition of PC synthesis causes PC depletion. Cellular perturbations like metabolic insults and unfolded proteins can be registered by the endoplasmic reticulum (ER) and result in ER stress responses, which can lead eventually to apoptosis. In this study we investigated the effect of PC depletion on the ER stress response and ER-related proteins. Shifting MT58 cells to the non-permissive temperature of 40°C resulted in PC depletion via an inhibition of CT within 24h. Early apoptotic features appeared in several cells around 30h, and most cells were apoptotic within 48h. The temperature shift in MT58 led to an increase of pro-apoptotic CCAAT/enhancer-binding protein-homologous protein (CHOP; also known as GADD153) after 16h, to a maximum at 24h. Incubation of wild-type CHO-K1 or CT-expressing MT58 cells at 40°C did not induce differences in CHOP protein levels in time. In contrast, expression of the ER chaperone BiP/GRP78, induced by an increase in misfolded/unfolded proteins, and caspase 12, a protease specifically involved in apoptosis that results from stress in the ER, did not differ between MT58 and CHO-K1 cells in time when cultured at 40°C. Furthermore, heat-shock protein 70, a protein that is stimulated by accumulation of abnormal proteins and heat stress, displayed similar expression patterns in MT58 and K1 cells. These results suggest that PC depletion in MT58 induces the ER-stress-related protein CHOP, without raising a general ER stress response.

scholarly journals Induction of CCAAT/Enhancer-binding Protein (C/EBP)-homologous Protein/Growth Arrest and DNA Damage-inducible Protein 153 Expression during Inhibition of Phosphatidylcholine Synthesis Is Mediated via Activation of a C/EBP-activating Transcription Factor-responsive Element

2004 ◽  
Vol 279 (50) ◽  
pp. 52007-52015 ◽  
Author(s):  
Michiel H. M. van der Sanden ◽  
Henriët Meems ◽  
Martin Houweling ◽  
J. Bernd Helms ◽  
Arie B. Vaandrager
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Protein C ◽  
Binding Protein ◽  
Growth Arrest ◽  
Homologous Protein ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Inducible Protein ◽  
Responsive Element

The gene for the proapoptotic transcription factor CCAAT/enhancer-binding protein (C/EBP)-homologous protein/growth arrest and DNA damage-inducible protein 153 (CHOP/GADD153) is induced by various cellular stresses. Previously, we described that inhibition of phosphatidylcholine (PC) synthesis in MT58 cells, which contain a temperature-sensitive mutation in CTP:phosphocholine cytidylyltransferase (CT), results in apoptosis preceded by the induction of CHOP. Here we report that prevention of CHOP induction, by expression of antisense CHOP, delays the PC depletion-induced apoptotic process. By mutational analysis of the conserved region in the promoter of the CHOP gene, we provide evidence that the C/EBP-ATF composite site, but not the ER stress-responsive element or the activator protein-1 site, is required for the increased expression of CHOP during PC depletion. Inhibition of PC synthesis in MT58 cells also led to an increase in phosphorylation of the stress-related transcription factor ATF2 and the stress kinase JNK after 8 and 16 h, respectively. In contrast, no phosphorylation of p38 MAPK was observed in MT58 cultured at the nonpermissive temperature. Treatment of MT58 cells with the JNK inhibitor SP600125 could rescue the cells from apoptosis but did not inhibit the phosphorylation of ATF2 or the induction of CHOP. Taken together, our results suggest that increased expression of CHOP during PC depletion depends on a C/EBP-ATF element in its promoter and might be mediated by binding of ATF2 to this element.

The effect of baicalein on endoplasmic reticulum stress and autophagy on liver damage

2021 ◽  
pp. 096032712110036
Author(s):  
MC Üstüner ◽  
C Tanrikut ◽  
D Üstüner ◽  
UK Kolaç ◽  
Z Özdemir Köroğlu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Liver Damage ◽  
Albino Rats ◽  
Tem Analysis ◽  
Stress Markers ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Wistar Albino Rats

Carbon tetrachloride (CCl4) is a toxic chemical that causes liver injury. CCl4 triggers endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR triggers autophagy to deal with the damage. The aim of this study was to investigate the effect of baicalein, derived from Scutellaria baicalensis, on CCl4-induced liver damage concerning ER stress and autophagy. Two groups of Wistar albino rats (n = 7/groups) were treated with 0.2 ml/kg CCl4 for 10 days with and without baicalein. Histological and transmission electron microscopy (TEM) analysis, autophagy, and ER stress markers measurements were carried out to evaluate the effect of baicalein. Histological examinations showed that baicalein reduced liver damage. TEM analysis indicated that baicalein inhibited ER stress and triggered autophagy. CCl4-induced elevation of C/EBP homologous protein (CHOP), glucose-regulating protein 78 (GRP78), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and active/spliced form of X-box-binding protein 1 (XBP1s) ER stress markers were decreased by baicalein. Baicalein also increased the autophagy-related 5 (ATG5), Beclin1, and Microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine-conjugated form (LC3-II) autophagy marker levels. In conclusion, baicalein reduced the CCl4-induced liver damage by inhibiting ER stress and the trigger of autophagy.

scholarly journals Acute Tissue Injury Caused by Subcutaneous Fat Biopsies Produces Endoplasmic Reticulum Stress

2009 ◽  
Vol 30 (7) ◽  
pp. 928-928
Author(s):  
Guenther Boden ◽  
Matthew Silviera ◽  
Brian Smith ◽  
Peter Cheung ◽  
Carol Homko
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Tissue Injury ◽  
Subcutaneous Fat ◽  
Whole Body ◽  
Monocyte Chemoattractant Protein 1 ◽  
Homologous Protein ◽  
Stress Markers ◽  
Acute Tissue Injury ◽  
Glucose Regulated Protein

Abstract Background It is not known whether acute tissue injury is associated with endoplasmic reticulum (ER) stress. Objective Our objective was to determine whether open, sc fat biopsies cause ER stress. Approach Five healthy subjects underwent three open sc fat biopsies. The first biopsy, taken from the lateral aspect of a thigh, was followed 4 h later by a second biopsy from the same incision site and a third biopsy from the contralateral leg. Expression markers of ER stress, inflammation, hypoxia, and adipokines were measured in these fat biopsies. In addition, we tested for signs of systemic ER stress and inflammation in plasma and in circulating monocytes. Results mRNA/18s ratios of IL-6, monocyte chemoattractant protein-1, CD-14, hypoxia-induced factor 1-α, the spliced form of Xbox protein-1, glucose-regulated protein 78, CEBP homologous protein, and activating factor-4 were all severalfold higher, whereas mRNA/18s ratios of adiponectin and leptin were lower in fat biopsies taken from the same site 4 h after the first biopsy but were unchanged in the second biopsy that was taken from the contralateral site. The biopsies were not associated with changes in plasma and monocyte IL-6 concentrations or in monocyte ER stress markers. Also, whole-body insulin-stimulated glucose uptake was the same in 15 subjects who had biopsies compared with 15 different subjects who did not. Conclusion Open, sc fat biopsies produced inflammation, hypoxia, ER stress, and decreased expression of adiponectin and leptin. These changes remained confined to the biopsy site for at least 4 h.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

PERK mediates oxidative stress and adipogenesis in Graves’ orbitopathy pathogenesis

2021 ◽  
Author(s):  
JaeSang Ko ◽  
Ji-Young Kim ◽  
Min Kyung Chae ◽  
Eun Jig Lee ◽  
Jin Sook Yoon
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Adipogenic Differentiation ◽  
Ros Generation ◽  
Mrna Levels ◽  
Graves Orbitopathy ◽  
Orbital Fibroblasts

We examined endoplasmic reticulum (ER) stress-related gene expression in orbital tissues from patients with Graves’ orbitopathy (GO) and the effects of silencing protein kinase RNA-like endoplasmic reticulum kinase (PERK) in primary orbital fibroblast cultures to demonstrate the therapeutic potential of PERK-modulating agents in GO management. The expression of ER stress related genes in orbital tissue harvested from individuals with or without GO was studied using real-time polymerase chain reaction. The role of PERK in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in cultured primary orbital fibroblasts. Intracellular reactive oxygen species (ROS) levels induced in response to cigarette smoke extract (CSE) or hydrogen peroxide were measured using 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. Cells were stained with Oil Red O, and adipogenesis-related transcription factor expression was evaluated through western blotting after adipogenic differentiation. PERK, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein (C/EBP)-homologous protein(CHOP)mRNA levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. PERK silencing inhibited CSE- or hydrogen peroxide-induced ROS generation. After adipogenic differentiation, GO orbital fibroblasts revealed decreased lipid droplets and downregulation of C/EBPα, C/EBPβ, and peroxisome proliferator-activator gamma (PPARγ) in PERK siRNA-transfected cells. The orbital tissues of patients with GO were exposed to chronic ER stress and subsequently exhibited enhanced unfolded protein response (especially through the PERK pathway). PERK silencing reduced oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. Our results imply that PERK-modulating agents can potentially be used to manage GO.

Autophagy triggers endoplasmic reticulum stress and C/EBP homologous protein-mediated apoptosis in OGD/R-treated neurons in a caspase-12-independent manner

2021 ◽  
Author(s):  
Ying Tian ◽  
Liang Wang ◽  
Zhiqiang Qiu ◽  
Yulun Xu ◽  
Rongrong Hua
Keyword(s):  
Endoplasmic Reticulum ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Homologous Protein ◽  
Caspase 12 ◽  
Induced Apoptosis

We reported that a high level of autophagy was initiated by oxygen-glucose deprivation (OGD) and was maintained in neurons even after oxygen-glucose deprivation followed by reoxygenation (OGD/R), accompanied by neuronal apoptosis. This study focused on autophagy-induced apoptosis and its signaling network, especially the role of endoplasmic reticulum stress (ERS). Analysis of primary cultured cortical neurons from mice showed that the autophagy-induced apoptosis depended on Caspase-8 and -9 but not Caspase-12. This finding did not mean that the endoplasmic reticulum did not participate in this process. Increases in the levels of endoplasmic reticulum (ER) biomarkers and Binding immunoglobulin protein (BiP) were induced by autophagy in OGD/R-treated neurons. In addition, as an apoptotic transcription factor induced by ER stress, C/EBP homologous protein (CHOP) expression was significantly increased in neurons after OGD/R. This result suggested that the autophagy-Bip-CHOP-caspase (8 and 9)-dependent apoptotic signaling pathway at least partly participated in autophagy-induced apoptosis in primary cortical neurons. It revealed that ER induced apoptosis in neurons suffering from OGD/R injury in an ER stress-CHOP-dependent manner rather than a caspase-12-dependent manner. However, more research on signaling or cross-linking networks and intermediate links are needed. The realization of caspase-12-independent BiP-CHOP neuronal apoptosis pathway has expanded our understanding of the neuronal apoptosis network, which may eventually provide endogenous interventional strategies for OGD/R injury after stroke.

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