PGJ<sub>2</sub>-stimulated β-cell apoptosis is associated with prolonged UPR activation

Chambers, Kari T.; Weber, Sarah M.; Corbett, John A.

doi:10.1152/ajpendo.00274.2006

Cited by 20 publications

(17 citation statements)

References 63 publications

(102 reference statements)

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“…While the increase in tunicamycin-induced death of RINm5F cells expressing UPR transducer mutants may appear to be somewhat attenuated when compared with the increase in death in the corresponding MEFs, it is the expected increase in the level of RINm5F cell death when the 60% transfection efficiency of the UPR transducer mutants is taken into account in these assays. These findings, which support previous studies indicating that UPR-mediated cell death is enhanced in the absence of a functional PERK response (23,33), provide direct evidence that cytokine-induced death can occur independent of UPR activation, as deletion of either PERK or IRE1␣ or expression of the S51A eIF2␣ mutant does not alter the levels of death in response to cytokine treatment.…”

Section: Diabetes Vol 57 January 2008supporting

confidence: 89%

“…In contrast, if the UPR participates in cytokine-mediated damage, then inactivation of UPR transducer activity would be expected to enhance cell death. We have previously shown that inhibition of PERK enhances caspase-3 activation in response to PGJ 2 (33), and Scheuner et al (23) demonstrated a 57% increase in tunicamycin-induced apoptosis of MEFs expressing a S51A mutation. Consistent with this hypothesis, there is no difference in the levels of cell death in wild-type, PERK Ϫ/Ϫ , S51A (A/A), and IRE1␣ Ϫ/Ϫ MEFs following a 24-h incubation with IL-1 and IFN-␥.…”

Section: Discussionmentioning

confidence: 93%

“…RINm5F cells were transiently transfected using the Amaxa Nucleofector electroporator (Amaxa Biosystems, Gaithersburg, MD) with 2 g pEGFP (enhanced green fluorescent protein) and pETFVA-eIF2␣ (S51A) or pcDNA3-PERK (K621M) as previously described (33). Using this method, we routinely obtain a transfection efficiency of 50 -60%, as determined by EGFP expression.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast to the effects of IL-1, the peroxisome proliferatoractivated receptor ␥ ligand PGJ 2 stimulates the processing of caspase-3 to the active mature protease. Importantly, we have recently shown that PGJ 2 activates the UPR and induces ␤-cell apoptosis in a caspase-3-dependent manner (33).…”

Section: Diabetes Vol 57 January 2008mentioning

confidence: 99%

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The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death

et al. 2008

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OBJECTIVE-The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress; however, prolonged UPR activation can result in apoptotic cell death. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate ␤-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced ␤-cell death was examined. RESEARCH DESIGN AND METHODS-The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies.RESULTS-UPR activation correlates with ␤-cell death in interleukin (IL)-1-treated rat islets. NO mediates both cytokineinduced UPR activation and ␤-cell death as NO synthase inhibitors attenuate each of these IL-1-stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce ␤-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity. In addition, cell death is enhanced by ϳ35% in tunicamycintreated cells expressing an S51A eIF2␣ mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulum-like kinase). In contrast, neither the absence of PERK nor the expression of the S51A eIF2␣ mutant affects the levels of cytokine-induced death.CONCLUSIONS-While cytokine-induced ␤-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced ␤-cell death. Diabetes 57:124-132, 2008

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Section: Diabetes Vol 57 January 2008supporting

confidence: 89%

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Diabetes Vol 57 January 2008mentioning

confidence: 99%

See 2 more Smart Citations

The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death

et al. 2008

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“…As shown in other systems, such factors could also induce Ire1 activation and other UPR components in certain cell types (17,(43)(44)(45)(46)(47)(48). A further cause for IRE1 or UPR activation may be to support cell proliferation (clonal expansion) that follows antigen receptor gene rearrangement in B and T cells.…”

Section: Cd8mentioning

confidence: 91%

B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway

Brunsing

Omori

Weber

et al. 2008

Journal of Biological Chemistry

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The unfolded protein response (UPR) signaling pathway regulates the functional capacity of the endoplasmic reticulum for protein folding. Beyond a role for UPR signaling during terminal differentiation of mature B cells to antibody-secreting plasma cells, the status or importance of UPR signaling during hematopoiesis has not been explored, due in part to difficulties in isolating sufficient quantities of cells at developmentally intermediate stages required for biochemical analysis. Following reconstitution of irradiated mice with hematopoietic cells carrying a fluorescent UPR reporter construct, we found that IRE1 nuclease activity for XBP1 splicing is active at early stages of Tand B-lymphocyte differentiation: in bone marrow pro-B cells and in CD4 ؉ CD8 ؉ double positive thymic T cells. IRE1 was not active in B cells at later stages. In T cells, IRE activity was not detected in the more mature CD4 ؉ T-cell population but was active in the CD8؉ cytotoxic T-cell population. Multiple signals are likely to be involved in activating IRE1 during lymphocyte differentiation, including rearrangement of antigen receptor genes. Our results show that reporter-transduced hematopoietic stem cells provide a quick and easy means to identify UPR signaling component activation in physiological settings.Pluripotent stem cells are constantly faced with critical decisions between self-renewal and starting to differentiate into various cell types (1, 2). Commitment of differentiating stem cells toward the various lineages is influenced by many factors, including microenvironment and external cues that are integrated into signaling pathways regulating transcriptional programs and protein production. Hematopoietic stem cells (HSC) 3 that differentiate into the erythroid, myeloid, or lymphoid lineages, primarily in the bone marrow of vertebrate adults, undergo dramatic changes in cellular architecture during differentiation to functionally specialized cells. For cells that are specialized for protein secretion, such changes include the creation of extraordinary protein processing and secretory apparatus. The unfolded protein response (UPR) is a conserved signal transduction pathway that in response to endoplasmic reticulum (ER) stress enables cells to increase the protein folding capacity of the ER, the major cellular compartment for folding and maturation of secreted and membrane proteins, by increasing the transcription of genes involved in protein folding. In addition, UPR activation also increases expression of genes involved in ER membrane biosynthesis, presumably resulting in ER expansion. Thus, UPR signaling may play a role in the differentiation of HSC. In fact, an importance for the UPR signaling components IRE1 and XBP1 has been demonstrated during the terminal differentiation of activated B lymphocytes (B cells) to immunoglobulin-secreting plasma cells (3-6).In mammalian cells, three ER transmembrane components, IRE1, PERK, and ATF6, serve to monitor ER protein folding needs and initiate UPR activation (7-10). In additio...

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Arachidonoyl‐ethanolamide activates endoplasmic reticulum stress‐apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase‐2 and novel J‐series prostamides

Soliman

Henderson

Danell

et al. 2015

Molecular Carcinogenesis

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Non-melanoma skin cancer and other epithelial tumors overexpress cyclooxygenase-2 (COX-2), differentiating them from normal cells. COX-2 metabolizes arachidonic acid to prostaglandins including, the J-series prostaglandins, which induce apoptosis by mechanisms including endoplasmic reticulum (ER) stress. Arachidonoyl-ethanolamide (AEA) is a cannabinoid that causes apoptosis in diverse tumor types. Previous studies from our group demonstrated that AEA was metabolized by COX-2 to J-series prostaglandins. Thus, the current study examines the role of COX-2, J-series prostaglandins, and ER stress in AEA-induced apoptosis. In tumorigenic keratinocytes that overexpress COX-2, AEA activated the PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE1), and activating transcription factor-6 (ATF6) ER stress pathways and the ER stress apoptosis-associated proteins, C/EBP homologous protein-10 (CHOP10), caspase-12, and caspase-3. Using an ER stress inhibitor, it was determined that ER stress was required for AEA-induced apoptosis. To evaluate the role of COX-2 in ER stress-apoptosis, HaCaT keratinocytes with low endogenous COX-2 expression were transfected with COX-2 cDNA or an empty vector and AEA-induced ER stress-apoptosis occurred only in the presence of COX-2. Moreover, LC-MS analysis showed that the novel prostaglandins, 15-deoxyΔ(12,14) PGJ2 -EA and Δ(12) PGJ2 /PGJ2-EA, were synthesized from AEA. These findings suggest that AEA will be selectively toxic in tumor cells that overexpress COX-2 due to the metabolism of AEA by COX-2 to J-series prostaglandin-ethanolamides (prostamides). Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX-2.

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PGJ₂-stimulated β-cell apoptosis is associated with prolonged UPR activation

Abstract: Chambers KT, Weber SM, Corbett JA. PGJ2-stimulated ␤-cell apoptosis is associated with prolonged UPR activation.

Cited by 20 publications

References 63 publications

The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death

The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death

B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway

Arachidonoyl‐ethanolamide activates endoplasmic reticulum stress‐apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase‐2 and novel J‐series prostamides

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PGJ2-stimulated β-cell apoptosis is associated with prolonged UPR activation

Abstract: Chambers KT, Weber SM, Corbett JA. PGJ2-stimulated ␤-cell apoptosis is associated with prolonged UPR activation.

Cited by 20 publications

References 63 publications

The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death

The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine-Induced β-Cell Death

B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway

Arachidonoyl‐ethanolamide activates endoplasmic reticulum stress‐apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase‐2 and novel J‐series prostamides

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PGJ₂-stimulated β-cell apoptosis is associated with prolonged UPR activation