scholarly journals FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis

2016 ◽  
Vol 39 (6) ◽  
pp. 2501-2508 ◽  
Author(s):  
Xi Chen ◽  
Lang-Huan Duan ◽  
Peng-cheng Luo ◽  
Gang Hu ◽  
Xin Yu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Critical Role ◽  
Dependent Manner ◽  
Ubiquitin E3 Ligase ◽  
The Stability ◽  
Induced Apoptosis ◽  
F Box Protein ◽  
Protein Disulfide

Background/Aims: FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex, recognizing the chitobiose in unfolded N-glycoprotein to target glycoproteins for polyubiquitination and degradation. Although how FBXO6 recognizes glycoprotein has been fully investigated, the ubiquitination substrates of FBXO6 remain largely unknown. Previously, we have systematically identified the glycoproteins that interact with FBXO6 in an N-glycan dependent manner by LC/MS spectrum and confirmed the interaction between FBXO6 and glycosylated Ero1L, a protein disulfide oxidase in endoplasmic reticulum (ER). Methods: The relationship between endogenous Ero1L and exogenous Flag-FBXO6 were determined by Western blot. In vivo ubiquitination assay was used to detect the direct effect of FBXO6 in the regulation of Ero1L. Both CCK8 and FACS assays were used to determine the apoptosis ratio of cells after treatments. Results: Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. Functionally, we show that FBXO6 inhibits ER stress-induced apoptosis by modulating the protein level of Ero1L. Conclusion: Collectively, our results demonstrate FBXO6 as a functional E3 ubiquitin ligase for Ero1L that plays a critical role in inhibiting ER stress-induced apoptosis.

scholarly journals MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 150 ◽  
Author(s):  
Hyun Lim ◽  
Moon Park ◽  
Changmin Kim ◽  
Beomku Kang ◽  
Hyo-Sook Song ◽  
...  
Keyword(s):  
Er Stress ◽  
Critical Role ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Parp Cleavage ◽  
Dependent Manner ◽  
U937 Cells ◽  
Anti Cancer ◽  
Spatholobus Suberectus ◽  
Induced Apoptosis ◽  
Related Proteins

Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer.

scholarly journals N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

2020 ◽  
Vol 21 (16) ◽  
pp. 5815
Author(s):  
Hongqing Xie ◽  
Xiaotong Li ◽  
Weiwei Yang ◽  
Liping Yu ◽  
Xiasen Jiang ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Er Stress ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Antineoplastic Effect ◽  
Tumor Tissues ◽  
Induced Apoptosis ◽  
Species Production

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.

scholarly journals The Molecular Mechanism of Endoplasmic Reticulum Stress-Induced Apoptosis in PC-12 Neuronal Cells: The Protective Effect of Insulin-Like Growth Factor I

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 277-285 ◽  
Author(s):  
Cheng-Gang Zou ◽  
Xiu-Zhen Cao ◽  
Yue-Shui Zhao ◽  
Shun-Yu Gao ◽  
Shu-De Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Er Stress ◽  
P38 Mapk ◽  
Neuronal Apoptosis ◽  
Neuronal Cells ◽  
Dependent Manner ◽  
Related Protein ◽  
Igf I ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases. Although CCAAT/enhancer-binding protein homologous protein (CHOP) has been shown to play a critical role in ER stress, the precise apoptosis cascade downstream of CHOP is unknown. In this report, we investigated the mechanism of ER stress-mediated apoptosis as well as the action of IGF-I in PC-12 neuronal cells. Our results demonstrated that tribbles-related protein 3 (TRB3), which is a target gene of CHOP, was responsible for tunicamycin (an ER stress inducer)-induced apoptosis. TRB3 could promote dephosphorylation of Akt in PC-12 cells. IGF-I inhibited ER stress-induced apoptosis by restoring the phosphorylation level of Akt. Both wortmannin (a phosphatidylinositide 3-kinase inhibitor) and SB 212090 (a p38 MAPK inhibitor) suppressed the protective effect of IGF-I on ER stress-induced apoptosis. Interestingly, IGF-I attenuated ER stress-mediated expression of TRB3 but not CHOP. This action of IGF-I was abolished by SB 212090 but not by wortmannin. Immunoprecipitation analysis revealed that IGF-I promoted the phosphorylation of CHOP by activating p38 MAPK, probably leading to a decrease in the transcriptional activity of CHOP. The dephosphorylation of Akt resulted in increased expression of a proapoptotic protein, p53 up-regulated modulator of apoptosis (PUMA), in a forkhead box O3a-dependent manner. Knockdown of PUMA by short hairpin RNA attenuated ER stress-mediated apoptosis. Thus, our current study indicates that both TRB3 and PUMA are critical molecules in ER stress-induced apoptosis. IGF-I effectively protects PC-12 neuronal cells against ER stress-induced apoptosis through the phosphatidylinositide 3-kinase/Akt and p38 MAPK pathways. Endoplasmic reticulum (ER) stress causes neuronal apoptosis by inducing the expression of tribbles-related protein 3 and PUMA. IGF-1 prevents neuronal apoptosis against ER stress through phosphatidylinositide 3-kinase/Akt and p38 mitogen-activated protein kinase pathways.

scholarly journals The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

2021 ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Critical Role ◽  
Er Stress Response ◽  
The Central Nervous System ◽  
The Brain

AbstractWhile ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca2+-binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system of Atf6b−/− mice, and restored by ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, calreticulin, Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in hippocampi of Atf6b−/− and Calr+/− mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+ homeostasis under ER stress.

scholarly journals p31 Deficiency Influences Endoplasmic Reticulum Tubular Morphology and Cell Survival

2009 ◽  
Vol 29 (7) ◽  
pp. 1869-1881 ◽  
Author(s):  
Takefumi Uemura ◽  
Takashi Sato ◽  
Takehiro Aoki ◽  
Akitsugu Yamamoto ◽  
Tetsuya Okada ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nuclear Translocation ◽  
Marked Change ◽  
Conditional Knockout ◽  
Induced Apoptosis ◽  
Factor C ◽  
Er Membrane

ABSTRACT p31, the mammalian orthologue of yeast Use1p, is an endoplasmic reticulum (ER)-localized soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) that forms a complex with other SNAREs, particularly syntaxin 18. However, the role of p31 in ER function remains unknown. To determine the role of p31 in vivo, we generated p31 conditional knockout mice. We found that homozygous deletion of the p31 gene led to early embryonic lethality before embryonic day 8.5. Conditional knockout of p31 in brains and mouse embryonic fibroblasts (MEFs) caused massive apoptosis accompanied by upregulation of ER stress-associated genes. Microscopic analysis showed vesiculation and subsequent enlargement of the ER membrane in p31-deficient cells. This type of drastic disorganization in the ER tubules has not been demonstrated to date. This marked change in ER structure preceded nuclear translocation of the ER stress-related transcription factor C/EBP homologous protein (CHOP), suggesting that ER stress-induced apoptosis resulted from disruption of the ER membrane structure. Taken together, these results suggest that p31 is an essential molecule involved in the maintenance of ER morphology and that its deficiency leads to ER stress-induced apoptosis.

scholarly journals Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis

2009 ◽  
Vol 186 (6) ◽  
pp. 783-792 ◽  
Author(s):  
Gang Li ◽  
Marco Mongillo ◽  
King-Tung Chin ◽  
Heather Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Calcium Release ◽  
Loss Of Function ◽  
Ip3 Receptor ◽  
Calcium Dependent ◽  
Insulin Resistant ◽  
Stressed Cells ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α in Chop−/− macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop−/− mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-α–IP3R pathway.

scholarly journals Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice

Bone ◽  
2015 ◽  
Vol 73 ◽  
pp. 60-68 ◽  
Author(s):  
Amy Y. Sato ◽  
Xiaolin Tu ◽  
Kevin A. McAndrews ◽  
Lilian I. Plotkin ◽  
Teresita Bellido
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Female Mice ◽  
Induced Apoptosis

Capsaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress

2011 ◽  
Vol 31 (6) ◽  
pp. 539-549 ◽  
Author(s):  
S-W Ip ◽  
S-H Lan ◽  
H-F Lu ◽  
A-C Huang ◽  
J-S Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Nasopharyngeal Carcinoma ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Dependent Manner ◽  
Mitochondrial Depolarization ◽  
Human Nasopharyngeal Carcinoma ◽  
Induced Apoptosis

Capsaicin, a pungent compound found in hot chili peppers, has been reported to have antitumor activities in many human cancer cell lines, but the induction of precise apoptosis signaling pathway in human nasopharyngeal carcinoma (NPC) cells is unclear. Here, we investigated the molecular mechanisms of capsaicin-induced apoptosis in human NPC, NPC-TW 039, cells. Effects of capsaicin involved endoplasmic reticulum (ER) stress, caspase-3 activation and mitochondrial depolarization. Capsaicin-induced cytotoxic effects (cell death) through G0/G1 phase arrest and induction of apoptosis of NPC-TW 039 cells in a dose-dependent manner. Capsaicin treatment triggered ER stress by promoting the production of reactive oxygen species (ROS), increasing levels of inositol-requiring 1 enzyme (IRE1), growth arrest and DNA-damage-inducible 153 (GADD153) and glucose-regulated protein 78 (GRP78). Other effects included an increase in cytosolic Ca2+, loss of the mitochondrial transmembrane potential (ΔΨ m), releases of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9 and -3. Furthermore, capsaicin induced increases in the ratio of Bax/Bcl-2 and abundance of apoptosis-related protein levels. These results suggest that ER stress- and mitochondria-mediated cell death is involved in capsaicin-induced apoptosis in NPC-TW 039 cells.

scholarly journals Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response

2019 ◽  
Vol 216 (6) ◽  
pp. 1431-1449 ◽  
Author(s):  
Hiroki Tanaka ◽  
Yasunobu Arima ◽  
Daisuke Kamimura ◽  
Yuki Tanaka ◽  
Noriyuki Takahashi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Target Genes ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mrna Degradation ◽  
Mutant Mice ◽  
Dependent Manner ◽  
T Helper 17 ◽  
External Stimuli

Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi–dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17–induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD) were resistant to the IL-17–mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17–mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.

scholarly journals Nck-dependent Activation of Extracellular Signal-regulated Kinase-1 and Regulation of Cell Survival during Endoplasmic Reticulum Stress

2004 ◽  
Vol 15 (9) ◽  
pp. 4248-4260 ◽  
Author(s):  
Duc Thang Nguyên ◽  
Sem Kebache ◽  
Ali Fazel ◽  
Hetty N. Wong ◽  
Sarah Jenna ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Er Stress ◽  
Cell Survival ◽  
Mapk Pathway ◽  
Critical Role ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

In response to stress, the endoplasmic reticulum (ER) signaling machinery triggers the inhibition of protein synthesis and up-regulation of genes whose products are involved in protein folding, cell cycle exit, and/or apoptosis. We demonstrate that the misfolding agents azetidine-2-carboxylic acid (Azc) and tunicamycin initiate signaling from the ER, resulting in the activation of Jun-N-terminal kinase, p44MAPK/extracellular signal-regulated kinase-1 (ERK-1), and p38MAPK through IRE1α-dependent mechanisms. To characterize the ER proximal signaling events involved, immuno-isolated ER membranes from rat fibroblasts treated with ER stress inducers were used to reconstitute the activation of the stress-activated protein kinase/mitogen-activate protein kinase (MAPK) pathways in vitro. This allowed us to demonstrate a role for the SH2/SH3 domain containing adaptor Nck in ERK-1 activation after Azc treatment. We also show both in vitro and in vivo that under basal conditions ER-associated Nck represses ERK-1 activation and that upon ER stress this pool of Nck dissociates from the ER membrane to allow ERK-1 activation. Moreover, under the same conditions, Nck-null cells elicit a stronger ERK-1 activation in response to Azc stress, thus, correlating with an enhanced survival phenotype. These data delineate a novel mechanism for the regulation of ER stress signaling to the MAPK pathway and demonstrate a critical role for Nck in ER stress and cell survival.

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