Diabetes Mellitus and Exocrine Pancreatic Dysfunction in Perk−/− Mice Reveals a Role for Translational Control in Secretory Cell Survival

Harding, Heather P.; Zeng, Huiqing; Zhang, Yuhong; Jungries, Rivka; Chung, Peter; Plesken, Heidi; Sabatini, David D.; Ron, David

doi:10.1016/s1097-2765(01)00264-7

Cited by 1,123 publications

(1,047 citation statements)

References 40 publications

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“…In contrast, the phenotype of CHOP À/À mice differs markedly from those of Ire1a À/À , XBP-1 À/À , PERK À/À and eIF2a S51A knockin mice. 18,40,45,[66][67][68] Ire1a À/À and XBP-1 À/À mice, which can induce ER chaperones upon ER stress, are embryonic lethal. 18,40,66 XBP-1 À/À livers show hypoplasia with numerous apoptotic hepatocytes, and XBP-1 À/À B cells fail to differentiate to plasma cells.…”

Section: Role Of Chop-mediated Apoptosis In Normal Cell Growth and DImentioning

confidence: 99%

“…66,69 PERK À/À and eIF2a S51A knockin mice have progressive pancreatic b-cell dysfunction due to increased apoptosis of the cells. 45,67,68 It should be noted that cells from PERK À/À and eIF2a S51A knockin mice are highly susceptible to ER stress; yet they are incapable of inducing CHOP upon ER stress. 45,46,70 Therefore, ER stress occurs under physiological conditions and the ER stress response plays an essential role in cell growth and differentiation.…”

Section: Role Of Chop-mediated Apoptosis In Normal Cell Growth and DImentioning

confidence: 99%

“…17,[74][75][76] PERK À/À mice develop progressive apoptosis in their b-cells and show marked hyperglycemia from 4 weeks of age. 67,68 Mutations in the PERK gene were identified, in patients with Wolcott-Rallison syndrome, as an autosomal recessive disease with severe infant diabetes due to pancreatic hypoplasia and a reduced number of b-cells. 77,78 eIF2a S51A knockin mice have more severe b-cell deficiency as seen in 16.5-18.5 embryos, and die within 18 h after birth due to hypoglycemia associated with defective gluconeogenesis.…”

Section: Diabetesmentioning

confidence: 99%

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Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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Section: Role Of Chop-mediated Apoptosis In Normal Cell Growth and DImentioning

confidence: 99%

Section: Role Of Chop-mediated Apoptosis In Normal Cell Growth and DImentioning

confidence: 99%

Section: Diabetesmentioning

confidence: 99%

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Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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“…Over the past decade, the endoplasmic reticulum (ER) has emerged as an important regulator of metabolic processes and recently has been implicated in the pathogenesis of endothelial dysfunction 6, 7, 8. The ER is a large, membrane‐enclosed cellular compartment, critical to the physiologic regulation of many cellular processes, including protein folding, lipid biosynthesis and redox homeostasis 9, 10, 11.…”

Section: Introductionmentioning

confidence: 99%

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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“…CHOP expression also is induced by the pancreatic endoplasmic reticulum kinase (PERK), an effect mediated by an increase in atf-4 translation [15,20]. Perk null mice and humans with perk gene mutations develop osteopenia due to increased osteoblast sensitivity to cellular stress, and atf4 null mice exhibit decreased bone formation due to impaired osteoblastic function [21,22].…”

Section: Introductionmentioning

confidence: 99%

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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Diabetes Mellitus and Exocrine Pancreatic Dysfunction in Perk−/− Mice Reveals a Role for Translational Control in Secretory Cell Survival

Cited by 1,123 publications

References 40 publications

Roles of CHOP/GADD153 in endoplasmic reticulum stress

Roles of CHOP/GADD153 in endoplasmic reticulum stress

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

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

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