scholarly journals Erratum: Corrigendum: IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tomozumi Takatani ◽  
Jun Shirakawa ◽  
Michael W. Roe ◽  
Colin A. Leech ◽  
Bernhard F. Maier ◽  
...  
Keyword(s):  
Er Stress ◽  
Protein Translation ◽  
Β Cells ◽  
Induced Apoptosis

scholarly journals IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tomozumi Takatani ◽  
Jun Shirakawa ◽  
Michael W. Roe ◽  
Colin A. Leech ◽  
Bernhard F. Maier ◽  
...  
Keyword(s):  
Er Stress ◽  
Protein Translation ◽  
Adaptor Proteins ◽  
Nuclear Accumulation ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Protein Instability ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Abstract Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the β-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca2+) was detected in IRS1KO β-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for β-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca2+ storage in the ER.

scholarly journals Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8016
Author(s):  
Tina Dahlby ◽  
Christian Simon ◽  
Marie Balslev Backe ◽  
Mattias Salling Dahllöf ◽  
Edward Holson ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Selective Inhibition ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Enhancer Of Zeste ◽  
Cell Gene Expression ◽  
Nfκb Pathway ◽  
Induced Apoptosis

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

Sirtuin-3 (SIRT3) protects pancreatic β-cells from endoplasmic reticulum (ER) stress-induced apoptosis and dysfunction

2016 ◽  
Vol 420 (1-2) ◽  
pp. 95-106 ◽  
Author(s):  
Hao-Hao Zhang ◽  
Xiao-Jun Ma ◽  
Li-Na Wu ◽  
Yan-Yan Zhao ◽  
Peng-Yu Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Sirtuin 3 ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Induced Apoptosis

scholarly journals JNK1/2 regulates ER–mitochondrial Ca2+ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

2013 ◽  
Vol 24 (12) ◽  
pp. 2058-2071 ◽  
Author(s):  
Gaurav Verma ◽  
Himanshi Bhatia ◽  
Malabika Datta
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Β Cells ◽  
Mediating Role ◽  
Induced Apoptosis

Elevated interleukin-1β (IL-1β) induces apoptosis in pancreatic β-cells through endoplasmic reticulum (ER) stress induction and subsequent c-jun-N-terminal kinase 1/2 (JNK1/2) activation. In earlier work we showed that JNK1/2 activation is initiated before ER stress and apoptotic induction in response to IL-1β. However, the detailed regulatory mechanisms are not completely understood. Because the ER is the organelle responsible for Ca2+ handling and storage, here we examine the effects of IL-1β on cellular Ca2+ movement and mitochondrial dysfunction and evaluate the role of JNK1/2. Our results show that in RINm5F cells and human primary β-cells, IL-1β alters mitochondrial membrane potential, mitochondrial permeability transition pore opening, ATP content, and reactive oxygen species production and these alterations are preceded by ER Ca2+ release via IP3R channels and mitochondrial Ca2+ uptake. All these events are prevented by JNK1/2 small interfering RNA (siRNA), indicating the mediating role of JNK1/2 in IL-1β–induced cellular alteration. This is accompanied by IL-1β–induced apoptosis, which is prevented by JNK1/2 siRNA and the IP3R inhibitor xestospongin C. This suggests a regulatory role of JNK1/2 in modulating the ER-mitochondrial-Ca2+ axis by IL-1β in apoptotic cell death.

scholarly journals Mitogen-Inducible Gene 6 Triggers Apoptosis and Exacerbates ER Stress-Induced β-Cell Death

2013 ◽  
Vol 27 (1) ◽  
pp. 162-171 ◽  
Author(s):  
Yi-Chun Chen ◽  
E. Scott Colvin ◽  
Bernhard F. Maier ◽  
Raghavendra G. Mirmira ◽  
Patrick T. Fueger
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Caspase 3 ◽  
Cell Mass ◽  
Growth Factor Receptor ◽  
Protein Translation ◽  
Β Cells ◽  
Β Cell ◽  
Inducible Gene

The increased insulin secretory burden placed on pancreatic β-cells during obesity and insulin resistance can ultimately lead to β-cell dysfunction and death and the development of type 2 diabetes. Mitogen-inducible gene 6 (Mig6) is a cellular stress-responsive protein that can negatively regulate the duration and intensity of epidermal growth factor receptor signaling and has been classically viewed as a molecular brake for proliferation. In this study, we used Mig6 heterozygous knockout mice (Mig6+/−) to study the role of Mig6 in regulating β-cell proliferation and survival. Surprisingly, the proliferation rate of Mig6+/− pancreatic islets was lower than wild-type islets despite having comparable β-cell mass and glucose tolerance. We thus speculated that Mig6 regulates cellular death. Using adenoviral vectors to overexpress or knockdown Mig6, we found that caspase 3 activation during apoptosis was dependent on the level of Mig6. Interestingly, Mig6 expression was induced during endoplasmic reticulum (ER) stress, and its protein levels were maintained throughout ER stress. Using polyribosomal profiling, we identified that Mig6 protein translation was maintained, whereas the global protein translation was inhibited during ER stress. In addition, Mig6 overexpression exacerbated ER stress-induced caspase 3 activation in vitro. In conclusion, Mig6 is transcriptionally up-regulated and resistant to global translational inhibition during stressed conditions in β-cells and mediates apoptosis in the form of caspase 3 activation. The sustained production of Mig6 protein exacerbates ER stress-induced β-cell death. Thus, preventing the induction, translation, and/or function of Mig6 is warranted for increasing β-cell survival.

PPARγ ligands induce ER stress in pancreatic β-cells: ER stress activation results in attenuation of cytokine signaling

2004 ◽  
Vol 287 (6) ◽  
pp. E1171-E1177 ◽  
Author(s):  
Sarah M. Weber ◽  
Kari T. Chambers ◽  
Kenneth G. Bensch ◽  
Anna L. Scarim ◽  
John A. Corbett
Keyword(s):  
Er Stress ◽  
Protective Action ◽  
Protein Translation ◽  
Initiation Factor ◽  
Cytokine Signaling ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Anti Inflammatory ◽  
Stress Activation

Peroxisome proliferator-activated receptor (PPAR)γ ligands are known to have anti-inflammatory properties that include the inhibition of cytokine signaling, transcription factor activation, and inflammatory gene expression. We have recently observed that increased expression of heat shock protein (HSP)70 correlates with, but is not required for, the anti-inflammatory actions of PPARγ ligands on cytokine signaling. In this study, we provide evidence that the inhibitory actions of PPARγ ligands on cytokine signaling are associated with endoplasmic reticulum (ER) stress or unfolded protein response (UPR) activation in pancreatic β-cells. 15-Deoxy-Δ12,14-prostaglandin J2, at concentrations that inhibit cytokine signaling, stimulates phosphorylation of eukaryotic initiation factor-2α, and this event is followed by a rapid inhibition of protein translation. Under conditions of impaired translation, PPARγ ligands stimulate the expression of a number of ER stress-responsive genes, such as GADD 153, BiP, and HSP70. Importantly, ER stress activation in response to PPARγ ligands or known UPR activators results in the attenuation of IL-1 and IFN-γ signaling. These findings indicate that PPARγ ligands induce ER stress, that ER stress activation is associated with an attenuation of cytokine signaling in β-cells, and that the attenuation of responsiveness to extracellular stimuli appears to be a novel protective action of the UPR in cells undergoing ER stress.

scholarly journals Novel protective effect of O-1602 and abnormal cannabidiol, GPR55 agonists, on ER stress-induced apoptosis in pancreatic β-cells

2019 ◽  
Vol 111 ◽  
pp. 1176-1186 ◽  
Author(s):  
Chi Teng Vong ◽  
Hisa Hui Ling Tseng ◽  
Yiu Wa Kwan ◽  
Simon Ming-Yuen Lee ◽  
Maggie Pui Man Hoi
Keyword(s):  
Protective Effect ◽  
Er Stress ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Induced Apoptosis

Xanthohumol Induces Apoptosis in B-CLL In Vitro by Sustained Endoplasmic Reticulum Stress and Inhibition of NFκ-B.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4979-4979
Author(s):  
Sofie Lust ◽  
Barbara Vanhoecke ◽  
Mireille Van Gele ◽  
Mary Kaileh ◽  
Jerina Boelens ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Caspase 3 ◽  
Protein Translation ◽  
Mrna Levels ◽  
Induced Apoptosis ◽  
Sustained Phosphorylation

Abstract Introduction Correct folding of new proteins is supervised in the endoplasic reticulum (ER) unfolded protein response (UPR). Misfolded proteins recruit the chaperone Grp78 that is thereby released from the transcription factors ATF6, IRE-1 leading to compensatory increase in Grp78, and PERK, leading to phosphorylation of eIF2α and block of further protein translation. UPR overload leads to ER stress and cell death. Targeting the endoplasmic reticulum (ER) is a new strategy explored in B-CLL. The hop-derived chalcone Xanthohumol (X) has been characterized as a ‘broad-spectrum’ cancer chemopreventive agent. Recently, we demonstrated that X induces dose- and time-dependent cell death of MCF7/6 breast cancer cells accompanied by ER stress. X induces apoptosis and cleavage of poly(ADP)-ribose-polymerase (PARP) in B-CLL in vitro. The present study investigates the branches of the UPR in relation to X induced apoptosis of B-CLL cells. Materials and methods. Lymphocytes were isolated by Lymphoprep from 15 patients with B-CLL after informed consent. CD19 positive cells were selected by EasySep positive selection kit. Apoptosis was assessed by flow-cytometry (AnnexinV-PI). Western Blotting was used for Grp78, ATF6, XBP1, phospho-eIF2a, eIF2a, ATF4, CHOP, phospho-IKK, IKK, PARP, caspase-9, -8, -7, -4, cleaved caspase-3, mcl-1, bcl-xL, bax, bak, and bid. NF-kB activity was assessed by EMSA. Quantitative RT-PCR was performed to analyze Grp78 mRNA levels. Bcl-2 protein level was detected by flow cytometry and reactive oxygen species (ROS) by fluorescence microscopy. Results and conclusion X induced an upregulation of Grp78 mRNA levels which was not translated in an increase in protein. X treatment stimulated a rapid and sustained phosphorylation of eIF2a, suggesting the involvement of PERK. In contrast, the ER-stress transducers ATF6 and IRE1 were not activated. X-induced ER stress was associated with strong induction of the pro-apoptotic protein CHOP and inhibition of the NF-kB pathway. Furthermore, the pro-apoptotic effect of X was accompanied by an accumulation of ROS, a downregulation of the anti-apoptotic proteins mcl-1, bcl-xL, bcl-2 and processing of caspase-3, -7 and -9.In conclusion, the chalcone X is capable of inducing cell death with down-regulation of bcl-2, mcl-1, bcl-xL, and activation of the caspase cascade. This is accompanied by ER-stress as evidenced by the upregulation of Grp78 mRNA levels, induction of a rapid and sustained phosphorylation of eIF2a, upregulation of CHOP, and inhibition of the NF-kB signaling.

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