scholarly journals Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ken-ichiro Tanaka ◽  
Misato Kasai ◽  
Mikako Shimoda ◽  
Ayane Shimizu ◽  
Maho Kubota ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Trace Metals ◽  
Er Stress ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Endoplasmic Reticulum Stress Response ◽  
Dependent Manner ◽  
Er Stress Response

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

Abstract 454: Endoplasmic Reticulum Stress Response in Pressure-Overloaded Ischemic-Reperfused Hearts

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Mahmood Mozaffari ◽  
Jun Yao Liu ◽  
Babak Baban
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Annexin V ◽  
Endoplasmic Reticulum Stress Response ◽  
Er Stress Response

An integral component of endoplasmic reticulum (ER) stress-induced apoptosis is expression of growth arrest- and DNA damage inducible protein 153 (GADD153); this protein is normally expressed in low levels but its expression markedly increases following sustained stress to the ER. GADD153 regulates both apoptosis and inflammatory response. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion (IR) injury. In this study, we tested the hypothesis that pressure overload regulates ER stress response manifested as increased GADD153 expression thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial IR injury. Accordingly, Langendorff-perfused rat hearts were subjected to global IR protocol with perfusion pressure set at 80 or 160 cmH 2 O; normoxic hearts served as controls. Compared to normoxia, an IR insult increased expressions of pro-inflammatory cytokine (interleukin (IL)-17) and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload a) increased expression of GADD153, b) reduced interleukin (IL)-10 but increased IL-17 and c) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Collectively, the results suggest that pressure overload exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of ER stress response and inflammation.

scholarly journals Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Fernanda L.B. Mügge ◽  
Aristóbolo M. Silva
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Endoplasmic Reticulum Stress Response ◽  
The Road ◽  
Er Stress Response ◽  
Mediated Effects ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractOver the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases’ therapy.

Targeting Proteinkinase C Alters ER-Stress and b-Catenin Signaling in Multiple Myeloma: Therapeutic Implications.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 258-258
Author(s):  
Marc S. Raab ◽  
Klaus Podar ◽  
Jing Zhang ◽  
Giovanni Tonon ◽  
Johannes H. Fruehauf ◽  
...  
Keyword(s):  
Cell Death ◽  
Stress Response ◽  
Growth Inhibition ◽  
Er Stress ◽  
Cell Lines ◽  
Wnt Pathway ◽  
Dependent Manner ◽  
P53 Family ◽  
Er Stress Response

Abstract We have previously shown that the novel orally available small molecule inhibitor of PKC enzastaurin (Eli Lilly and Company) inhibits MM cell growth, survival and angiogenesis both in vitro and in vivo. To date, however, the downstream effects contributing to growth inhibition and cell death remain to be determined. Here, we performed global gene expression profiling on enzastaurin treated MM cells and identified 200 Genes to be differentially regulated with a > 2-fold cut off. Strikingly, two major groups of up-regulated probe sets were associated with either of two pathways - endoplasmatic reticulum (ER)-stress response or WNT-signaling. Importantly, MM cells, producing high levels of paraprotein, are highly susceptible to perturbation of ER function and protein folding. Moreover, PKC isoforms have been reported to directly regulate the canonical WNT pathway via phosphorylation of b-catenin (CAT), leading to its ubiquination and proteasomal degradation. Specifically, we fist evaluated the role of enzastaurin in mediating ER-stress in MM cells. The transcriptional up-regulation of genes involved in ER-stress (GADD153/CHOP, GADD34, ATF3), triggered by enzastaurin at 3h, was confirmed by western blot analysis, accompanied by induction of the molecular ER chaperone BiP/grp78, phosphorylation of eIF2a consistent with PERK activation, and up-regulation of p21. These events were preceded by an early (1h) increase of intracellular calcium levels, a hallmark of ER-stress, assessed by FLUO4 staining. These data suggest an important role of ER-stress response in the early growth inhibition of MM cells caused by enzastaurin. Second, we delineated effects of enzastaurin on WNT pathway in MM and other tumor cell lines. Upon enzastaurin treatment, CAT was dephosphorylated at Ser33, 37, 41 in a dose- and time-dependent manner in all cell lines tested (10 MM, 3 colon cancer, HeLa, as well as human embryonic kidney 293 cells). Consequently, accumulation of CAT occurred in both cytosolic and nuclear fractions of treated MM cells, associated with activated TOPflash LUC-reporter system, confirming nuclear transactivating activity. Specific inhibition of CAT by siRNA partially rescued HeLa, HEK 293, and MM cells from cell death induced by enzastaurin. Analysis of downstream target molecules revealed a CAT-dependent up-regulation of c-Jun, but not of c-Myc or Cyclin D1. c-Jun has been reported to stabilize p73, a pro-apoptotic p53-family member; CAT induction by enzastaurin led to p73 (but not p53) activation and was also abrogated by CAT-specific siRNA. In turn, specific knockdown of p73 by siRNA rescued cells from enzastaurin-induced apoptosis. Finally, ectopic overexpression of CAT in HeLa and MM cells induced c-Jun expression and p73 activation, followed by apoptotic cell death. Our studies therefore indicate that ER-stress response contributes to the immediate inhibition of proliferation by enzastaurin, followed by CAT accumulation leading to p73 activation, contributing to enzastaurin-mediated cell death. These findings provide a novel link between CAT and p53-family members. Moreover p73, which is only rarely mutated in human cancers, represents a novel therapeutic target in MM.

scholarly journals Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

2003 ◽  
Vol 23 (10) ◽  
pp. 1117-1128 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Protein Modification ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Transgenic Animals ◽  
Initiation Factor

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

scholarly journals Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

2011 ◽  
Vol 286 (28) ◽  
pp. 24743-24753 ◽  
Author(s):  
Geum-Hwa Lee ◽  
Do-Sung Kim ◽  
Hyung-Tae Kim ◽  
Jung-Wook Lee ◽  
Chin-Ha Chung ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Lysosomal Activity ◽  
Er Stress Response

scholarly journals PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Myong-Ho Jeong ◽  
Hyeon-Ju Jeong ◽  
Byeong-Yun Ahn ◽  
Jung-Hoon Pyun ◽  
Ilmin Kwon ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Regulatory Mechanism ◽  
Critical Role ◽  
Mechanistic Study ◽  
Stress Signaling ◽  
Deficient Mutant ◽  
Er Stress Response

AbstractEndoplasmic reticulum (ER) stress signaling plays a critical role in the control of cell survival or death. Persistent ER stress activates proapoptotic pathway involving the ATF4/CHOP axis. Although accumulating evidences support its important contribution to cardiovascular diseases, but its mechanism is not well characterized. Here, we demonstrate a critical role for PRMT1 in the control of ER stress in cardiomyocytes. The inhibition of PRMT1 augments tunicamycin (TN)-triggered ER stress response in cardiomyocytes while PRMT1 overexpression attenuates it. Consistently, PRMT1 null hearts show exacerbated ER stress and cell death in response to TN treatment. Interestingly, ATF4 depletion attenuates the ER stress response induced by PRMT1 inhibition. The methylation-deficient mutant of ATF4 with the switch of arginine 239 to lysine exacerbates ER stress accompanied by enhanced levels of proapoptotic cleaved Caspase3 and phosphorylated-γH2AX in response to TN. The mechanistic study shows that PRMT1 modulates the protein stability of ATF4 through methylation. Taken together, our data suggest that ATF4 methylation on arginine 239 by PRMT1 is a novel regulatory mechanism for protection of cardiomyocytes from ER stress-induced cell death.

scholarly journals Endoplasmic Reticulum Stress and Parkinson’s Disease: The Role of HRD1 in Averting Apoptosis in Neurodegenerative Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Tomohiro Omura ◽  
Masayuki Kaneko ◽  
Yasunobu Okuma ◽  
Kazuo Matsubara ◽  
Yasuyuki Nomura
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Causative Factor ◽  
6 Hydroxydopamine

Endoplasmic reticulum (ER) stress has been known to be involved in the pathogenesis of various diseases, particularly neurodegenerative disorders such as Parkinson’s disease (PD). We previously identified the human ubiquitin ligase HRD1 that is associated with protection against ER stress and its associated apoptosis. HRD1 promotes the ubiquitination and degradation of Parkin-associated endothelin receptor-like receptor (Pael-R), an ER stress inducer and causative factor of familial PD, thereby preventing Pael-R-induced neuronal cell death. Moreover, upregulation of HRD1 by the antiepileptic drug zonisamide suppresses 6-hydroxydopamine-induced neuronal cell death. We review recent progress in the studies on the mechanism of ER stress-induced neuronal death related to PD, particularly focusing on the involvement of HRD1 in the prevention of neuronal death as well as a potential therapeutic approach for PD based on the upregulation of HRD1.

scholarly journals Characterization and modulation of endoplasmic reticulum stress response target genes in Kluyveromyces marxianus to improve secretory expressions of heterologous proteins

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Tianfang Shi ◽  
Jungang Zhou ◽  
Aijuan Xue ◽  
Hong Lu ◽  
Yungang He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Kluyveromyces Marxianus ◽  
Target Genes ◽  
Endoplasmic Reticulum Stress Response ◽  
Cell Factory ◽  
Heterologous Proteins ◽  
Er Stress Response ◽  
Response Target

Abstract Background Kluyveromyces marxianus is a promising cell factory for producing bioethanol and that raised a demand for a high yield of heterologous proteins in this species. Expressions of heterologous proteins usually lead to the accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER) and then cause ER stress. To cope with this problem, a group of ER stress response target genes (ESRTs) are induced, mainly through a signaling network called unfolded protein response (UPR). Characterization and modulation of ESRTs direct the optimization of heterologous expressions. However, ESRTs in K. marxianus have not been identified so far. Results In this study, we characterized the ER stress response in K. marxianus for the first time, by using two ER stress-inducing reagents, dithiothreitol (DTT) and tunicamycin (TM). Results showed that the Kar2–Ire1–Hac1 pathway of UPR is well conserved in K. marxianus. About 15% and 6% of genes were upregulated during treatment of DTT and TM, respectively. A total of 115 upregulated genes were characterized as ESRTs, among which 97 genes were identified as UPR target genes and 37 UPR target genes contained UPR elements in their promoters. Genes related to carbohydrate metabolic process and actin filament organization were identified as new types of UPR target genes. A total of 102 ESRTs were overexpressed separately in plasmids and their effects on productions of two different lignocellulolytic enzymes were systematically evaluated. Overexpressing genes involved in carbohydrate metabolism, including PDC1, PGK and VID28, overexpressing a chaperone gene CAJ1 or overexpressing a reductase gene MET13 substantially improved secretion expressions of heterologous proteins. Meanwhile, overexpressing a novel gene, KLMA_50479 (named ESR1), as well as overexpressing genes involved in ER-associated protein degradation (ERAD), including HRD3, USA1 andYET3, reduced the secretory expressions. ESR1 and the aforementioned ERAD genes were deleted from the genome. Resultant mutants, except the yet3Δ mutant, substantially improved secretions of three different heterologous proteins. During the fed-batch fermentation, extracellular activities of an endoxylanase and a glucanase in hrd3Δ cells improved by 43% and 28%, respectively, compared to those in wild-type cells. Conclusions Our results unveil the transcriptional scope of the ER stress response in K. marxianus and suggest efficient ways to improve productions of heterologous proteins by manipulating expressions of ESRTs.

scholarly journals Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

2005 ◽  
Vol 25 (1) ◽  
pp. 41-53 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Neuronal Degeneration ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Wild Type ◽  
Transgenic Rats ◽  
The Brain

The endoplasmic reticulum (ER), which plays a role in apoptosis, is susceptible to oxidative stress. Because superoxide is produced in the brain after ischemia/reperfusion, oxidative injury to this organelle may be implicated in ischemic neuronal cell death. Activating transcription factor-4 (ATF-4) and C/EBP-homologous protein (CHOP), both of which are involved in apoptosis, are induced by severe ER stress. Using wild-type and human copper/zinc superoxide dismutase transgenic rats, we observed induction of these molecules in the brain after global cerebral ischemia and compared them with neuronal degeneration. In ischemic, wild-type brains, expression of ATF-4 and CHOP was increased in the hippocampal CA1 neurons that would later undergo apoptosis. Transgenic rats had a mild increase in ATF-4 and CHOP and minimal neuronal degeneration, indicating that superoxide was involved in ER stress-induced cell death. We further confirmed attenuation on induction of these molecules in transgenic mouse brains after focal ischemia. When superoxide was visualized with ethidium, signals for ATF-4 and superoxide overlapped in the same cells. Moreover, lipids in the ER were robustly peroxidized by ischemia but were attenuated in transgenic animals. This indicates that superoxide attacked and damaged the ER, and that oxidative ER damage is implicated in ischemic neuronal cell death.

scholarly journals The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

2021 ◽  
Author(s):  
Kashi Raj Bhattarai ◽  
Thoufiqul Alam Riaz ◽  
Hyung-Ryong Kim ◽  
Han-Jung Chae
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Stress Response ◽  
Er Stress ◽  
Protein Modification ◽  
Endoplasmic Reticulum Stress Response ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

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