Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells

Pirot, Pierre; Ortis, Fernanda; Cnop, Miriam; Ma, Yanju; Hendershot, Linda M.; Eizirik, Décio L.; Cardozo, Alessandra K

doi:10.2337/db06-1253

Cited by 95 publications

(96 citation statements)

References 54 publications

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“…This hypothesis is supported by the fact that Xbp1 knockdown had no effect on the expression of the ERstress markers Bip and Chop, the latter a transcription factor shown to be increased in beta cells under pro-apoptotic ERstress [15,19]. This is in line with previous studies showing that XBP1s is not required for normal development of islets [40] while it is essential to development of liver [35] and plasma cells [41].…”

Section: Discussionsupporting

confidence: 86%

“…The sarco/endoplasmic reticulum calcium ATPase-2 inhibitor, cyclopiazonic acid (CPA) (Sigma-Aldrich, Bornem, Belgium), which induces rapid depletion of ER Ca 2+ thus leading to ER-stress was dissolved in DMSO and used at a concentration of 25 μmol/l in beta cells and 50 μmol/l in 208F [2,19] Generation of recombinant adenoviruses and cell infection To produce XBP1 in insulin-secreting cells, we generated recombinant adenoviruses comprising fragments of the mouse Xbp1 (mXbp1) mRNA (gi|18139942|gb| AF443192.1) [20]. The following primers (Electronic supplementary material [ESM] Fig.…”

Section: Methodsmentioning

confidence: 99%

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Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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Aims/hypothesis Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)-C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis.Methods Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated.

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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“…Cytokine-induced JNK activity is involved in b-cell apoptosis 7 and cytokineinduced CHOP expression in b-cells is regulated at least in part by JNK. 18 We performed a time-course analysis of IL-1b þ IFN-g-induced CHOP in the presence or absence of the chemical JNK inhibitor SP600125. 14 JNK inhibition partly, but significantly, hindered CHOP overexpression after 15 and 24 h of treatment, thus confirming that cytokineinduced CHOP overexpression is partly JNK-dependent (Supplementary Figure S4A).…”

Section: Resultsmentioning

confidence: 99%

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

et al. 2012

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Induction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic b-cells. Pro-inflammatory cytokines are early mediators of b-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in b-cells, but the role for CHOP overexpression in cytokine-induced b-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-jB (NF-jB) is a crucial transcription factor regulating b-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-jB activity and expression of key NF-jB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IjB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting b-cell death: (1) CHOP directly contributes to cytokine-induced b-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-jB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis. Type 1 diabetes (T1D) is a severe chronic disease resulting from an autoimmune destruction of the pancreatic b-cells. The incidence of T1D has been rising steadily in developed countries from the 1950s to the present day, with the recent, alarming prediction that it will double in children under the age of 5 years by 2020. 1 b-cell loss in T1DM occurs slowly over years and 480% of the b-cell mass is usually lost at the time of diagnosis. Because of the excessive mortality associated with complications of T1D and the increasing incidence of childhood diabetes, 2 there is an ongoing effort to develop novel strategies for a better treatment and hopefully, prevention of T1D.In T1D, b-cells cooperate with the immune system to its own destruction by activating pro-apoptotic pathways and secreting chemokines/cytokines that contribute to islet inflammation. 3 These responses are mostly triggered via the secretion of the pro-inflammatory cytokines interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g) by the infiltrated immune cells. The mechanisms regulating cytokine-mediated b-cell apoptosis and pro-inflammatory responses are intricate and include, but are not restricted to, the activation of the transcription factors nuclear factor-kB (NF-kB) and STAT-1, the c-Jun N-terminal kinases (JNK), endoplasmic reticulum (ER) stress pathways and the intrinsic mitochondrial apoptotic pathways. [3][4][5][6][7] NF-kB activation is due to cytokine-dependent activation of the inhibitor of k-light polypeptide gene enha...

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“…Moreover, a recent study has shown that in the Akita mouse model of diabetes, a mutation in Ins2 resulted in misfolding of the insulin protein causing ER stress and beta cell apoptosis [37]. Chronic exposure of islets and beta cells to fatty acids is known to cause dysfunction and cellular death [38], and this apoptosis has recently been shown to be the result of activation of an ER stress response [39][40][41]. Interestingly, ER stress markers have also been shown to be increased in islets from patients with type 2 diabetes [41,42], implicating ER stress as a contributor to beta cell dysfunction in humans.…”

Section: Possible Mechanisms That Could Explain Hypersecretion-inducementioning

confidence: 99%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells

Cited by 95 publications

References 54 publications

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

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