CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum

Zinszner, Hélène; Kuroda, Masahiko; Wang, XiaoZhong; Batchvarova, Nikoleta; Lightfoot, Richard; Remotti, Helen; Stevens, James; Ron, David

doi:10.1101/gad.12.7.982

Cited by 1,851 publications

(1,636 citation statements)

References 49 publications

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“…Consequently, technical reasons did not allow us to correct labeled cells/trabecular bone area. The results are in agreement with the known effects of CHOP on programmed cell death in response to ER stress [14,40,41]. ER stress induces CHOP expression and phosphorylation, and the constitutive overexpression of CHOP in cultured cells sensitizes them to ER stress favoring cellular death and impairing cellular functions [40,42].…”

Section: Discussionsupporting

confidence: 88%

“…The results observed mimic those reported in chondrocytes following the induction of ER stress, which causes chondrocytic apoptosis, and decreased extracellular matrix synthesis and type II collagen production [42]. Although impaired cell growth also occurs during ER stress responses, and presumably is mediated by CHOP, this did not occur in CHOP overexpressing mice, as BrdU labeling was not different from control wild types [14,42,43]. This could be because of differences in the cells and models studied or because the impaired cell growth observed during ER stress response is mediated by CHOP, but requires the presence of additional cellular signals.…”

Section: Discussionsupporting

confidence: 83%

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CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Pereira

Stadmeyer

Smith

et al. 2007

Bone

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CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), is a member of the C/EBP family of nuclear proteins and plays a role in osteoblastic and adipocytic cell differentiation. CHOP is necessary for normal bone formation, but the consequences of its overexpression in vivo are not known. To investigate the direct actions of CHOP on bone remodeling in vivo, we generated transgenic mice overexpressing CHOP under the control of the human osteocalcin promoter. CHOP transgenics exhibited normal weight and reduced bone mineral density. Static and dynamic femoral bone histomorphometry revealed that CHOP overexpression caused reduced trabecular bone volume, secondary to decreased bone formation rates. One of 2 lines displayed a decrease in the number of osteoblasts, but in vivo bromodeoxyuridine labeling demonstrated that CHOP overexpression did not have an effect on osteoblastic cell replication. The decreased osteoblast cell number was accounted by an increase in apoptosis, as determined by DNA fragmentation measured by transferase-mediated digoxigenin-deoxyuridine triphosphate (dUTP) in situ nick-end labeling (TUNEL) reaction. In conclusion, transgenic mice overexpressing CHOP in the bone microenvironment have impaired osteoblastic function leading to osteopenia.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 83%

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Pereira

Stadmeyer

Smith

et al. 2007

Bone

View full text Add to dashboard Cite

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“…In the present study, we develop evidence that ER stress pathways may be an important regulator of JNK activation in the vasculature in patients with DM by demonstrating increased activation of both the IRE1α and PERK pathways. Prolonged ER stress results in the induction of the pro‐apoptotic transcription factor CHOP, regarded as a key mediator of cell death, endothelial impairment, and disease in response to ER overload 27, 46, 47, 48. In the present study, we showed an enhanced expression of CHOP in the vascular endothelium of patients with DM when compared with controls without DM.…”

Section: Discussionsupporting

confidence: 61%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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BackgroundPrior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues from patients with diabetes mellitus (DM). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown.Methods and ResultsTo characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/EBPα‐homologous protein (P=0.02), were activated in patients with DM. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (P=0.025) in endothelial cells from patients with DM. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with DM (P=0.019).ConclusionsIn summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM.

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“…Interestingly, kidneys of CHOP −/− mice showed less evidence of cell death when treated with cisplatin (Zinszner et al. 1998). Despite these investigations, the precise mechanism(s) whereby cisplatin is able to induce ER stress is still unknown.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, some of the aforementioned studies brought causal relationship by using CHOP ‐/‐ mice or cells (Zinszner et al. 1998; Marciniak et al. 2004; Wu et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum

Cited by 1,851 publications

References 49 publications

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Role of endoplasmic reticulum stress in drug‐induced toxicity

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