15 results on '"Jaeseok Han"'
Search Results
2. Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin
- Author
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Siyoung Yang, Jaeseok Han, Ye Jin Park, Dong Wook Choi, Cheol Yong Choi, and Sang Woo Cho
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Programmed cell death ,RACK1 ,eIF2α ,Apoptosis ,Cytoplasmic Granules ,Receptors for Activated C Kinase ,stress granule ,Article ,Catalysis ,Inorganic Chemistry ,Biological pathway ,lcsh:Chemistry ,eIF-2 Kinase ,Stress granule ,Neoplasms ,Organelle ,Humans ,Physical and Theoretical Chemistry ,Receptor ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Ribonucleoprotein ,Flavonoids ,Chemistry ,Organic Chemistry ,General Medicine ,morusin ,PKR ,HCT116 Cells ,Protein kinase R ,Neoplasm Proteins ,Computer Science Applications ,Cell biology ,cell death ,lcsh:Biology (General) ,lcsh:QD1-999 ,PC-3 Cells ,Cancer cell ,HeLa Cells - Abstract
Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2&alpha, phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.
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- 2020
3. Characterization of Endoplasmic Reticulum (ER) in Human Pluripotent Stem Cells Revealed Increased Susceptibility to Cell Death upon ER Stress
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Man Ryul Lee, Byung Hoo Song, Ji Hun Jeong, Jacob H. Hanna, Hyeonseok Shin, Jeong Suk Im, Hyun Kyu Kim, Jaeseok Han, Dong Hun Woo, Jae-Sang Oh, and Tae Won Ha
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Pluripotent Stem Cells ,Thapsigargin ,Somatic cell ,Cellular differentiation ,C/EBP homologous protein (CHOP) ,Apoptosis ,Endoplasmic Reticulum ,Article ,chemistry.chemical_compound ,Humans ,human pluripotent stem cells ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,proteostasis ,biology ,Cell Death ,Chemistry ,Endoplasmic reticulum ,General Medicine ,binding immunoglobulin protein (BiP) ,Fibroblasts ,Endoplasmic Reticulum Stress ,Embryonic stem cell ,Cell biology ,endoplasmic reticulum (ER) ,lcsh:Biology (General) ,Unfolded protein response ,biology.protein ,CCAAT-Enhancer-Binding Proteins ,Unfolded Protein Response ,Binding immunoglobulin protein ,ER stress ,Signal Transduction - Abstract
Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have a well-orchestrated program for differentiation and self-renewal. However, the structural features of unique proteostatic-maintaining mechanisms in hPSCs and their features, distinct from those of differentiated cells, in response to cellular stress remain unclear. We evaluated and compared the morphological features and stress response of hPSCs and fibroblasts. Compared to fibroblasts, electron microscopy showed simpler/fewer structures with fewer networks in the endoplasmic reticulum (ER) of hPSCs, as well as lower expression of ER-related genes according to meta-analysis. As hPSCs contain low levels of binding immunoglobulin protein (BiP), an ER chaperone, thapsigargin treatment sharply increased the gene expression of the unfolded protein response. Thus, hPSCs with decreased chaperone function reacted sensitively to ER stress and entered apoptosis faster than fibroblasts. Such ER stress-induced apoptotic processes were abolished by tauroursodeoxycholic acid, an ER-stress reliever. Hence, our results revealed that as PSCs have an underdeveloped structure and express fewer BiP chaperone proteins than somatic cells, they are more susceptible to ER stress-induced apoptosis in response to stress.
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- 2020
4. PERK-mediated induction of microRNA-483 disrupts cellular ATP homeostasis during the unfolded protein response
- Author
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Karen Chiang, Jeffrey J. Rodvold, Jonathan H. Lin, Maurizio Zanetti, Nobuhiko Hiramatsu, Ji-Min Lee, Edward H. Koo, Leon Chea, Jaeseok Han, and Cathrine Aivati
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0301 basic medicine ,Programmed cell death ,endocrine system ,Apoptosis ,Activating Transcription Factor 4 ,Biochemistry ,03 medical and health sciences ,eIF-2 Kinase ,Adenosine Triphosphate ,Creatine Kinase, BB Form ,Gene silencing ,Homeostasis ,Humans ,Molecular Biology ,Transcription factor ,030102 biochemistry & molecular biology ,Kinase ,Chemistry ,Endoplasmic reticulum ,ATF4 ,Molecular Bases of Disease ,Cell Biology ,Cell biology ,MicroRNAs ,030104 developmental biology ,HEK293 Cells ,Unfolded protein response ,Unfolded Protein Response ,HeLa Cells - Abstract
Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which reduces levels of misfolded proteins. However, if ER homeostasis is not restored and the UPR remains chronically activated, cells undergo apoptosis. The UPR regulator, PKR-like endoplasmic reticulum kinase (PERK), plays an important role in promoting cell death when persistently activated; however, the underlying mechanisms are poorly understood. Here, we profiled the microRNA (miRNA) transcriptome in human cells exposed to ER stress and identified miRNAs that are selectively induced by PERK signaling. We found that expression of a PERK-induced miRNA, miR-483, promotes apoptosis in human cells. miR-483 induction was mediated by a transcription factor downstream of PERK, activating transcription factor 4 (ATF4), but not by the CHOP transcription factor. We identified the creatine kinase brain-type (CKB) gene, encoding an enzyme that maintains cellular ATP reserves through phosphocreatine production, as being repressed during the UPR and targeted by miR-483. We found that ER stress, selective PERK activation, and CKB knockdown all decrease cellular ATP levels, leading to increased vulnerability to ER stress-induced cell death. Our findings identify miR-483 as a downstream target of the PERK branch of the UPR. We propose that disruption of cellular ATP homeostasis through miR-483-mediated CKB silencing promotes ER stress-induced apoptosis.
- Published
- 2019
5. Modulation of Protein Synthesis by eIF2α Phosphorylation Protects Cell from Heat Stress-Mediated Apoptosis
- Author
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Ji-Min Lee, Rosalie Elvira, Duckgue Lee, Yohan Lim, So-Young Park, Man Ryul Lee, and Jaeseok Han
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0301 basic medicine ,Programmed cell death ,Chemistry ,Endoplasmic reticulum ,translation ,General Medicine ,Cycloheximide ,Article ,Cell biology ,heat stress ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Proteostasis ,lcsh:Biology (General) ,Apoptosis ,Homoharringtonine ,Unfolded protein response ,Signal transduction ,eIF2α phosphorylation ,ER stress ,unfolded protein response (UPR) ,lcsh:QH301-705.5 ,030217 neurology & neurosurgery - Abstract
Global warming poses a considerable threat to human health, necessitating a proper understanding of mechanisms underlying cell death in the pathogenesis of heat-related diseases. Although mechanisms governing cytoplasmic response to heat are well understood, processes regulating cellular response to disruption of proteostasis in the endoplasmic reticulum (ER) due to heat stress remain unclear. The current study reveals that hyperthermic conditions may lead to a disturbance of ER homeostasis, also known as ER stress. Subsequent activation of the unfolded protein response (UPR) resulted in concomitant induction of cell death. Among the three UPR signaling pathways, the eIF2α phosphorylation pathway, and not the IRE1α/ATF6α pathways, is likely the main contributor to cell death under heat stress. Considering the role of eIF2α in translational control, we investigated the protective effect of translation rate on heat stress-mediated cell death. When protein synthesis was attenuated using cycloheximide or homoharringtonine, cell death due to heat stress was significantly reduced. In summation, we propose that transient modulation of protein synthesis by eIF2α phosphorylation has a pivotal role in protecting cells from heat stress-induced apoptosis. Therefore, pharmacological agents that promote eIF2α phosphorylation or reduce ER stress may contribute to the development of promising therapeutic approaches against heat-related diseases.
- Published
- 2018
6. C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis
- Author
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Jing Yong, Erin M. Kropp, Harmeet Malhi, Vinna F. Clavo, Christina R. Kobrossi, Amy S. Mauer, Randal J. Kaufman, and Jaeseok Han
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Blood Glucose ,Male ,genetic structures ,Cell Survival ,Apoptosis ,Mice, Transgenic ,CHOP ,Biology ,Endoplasmic Reticulum ,Biochemistry ,Proinflammatory cytokine ,Mice ,immune system diseases ,hemic and lymphatic diseases ,Nonalcoholic fatty liver disease ,polycyclic compounds ,medicine ,Animals ,Obesity ,Molecular Biology ,Inflammation ,Transcription Factor CHOP ,Liver injury ,Macrophages ,Fatty liver ,Molecular Bases of Disease ,Cell Biology ,Endoplasmic Reticulum Stress ,medicine.disease ,Fibrosis ,eye diseases ,Fatty Liver ,PPAR gamma ,Liver ,Lipotoxicity ,Immunology ,Cancer research ,Female ,Steatohepatitis - Abstract
Nonalcoholic fatty liver disease is a heterogeneous disorder characterized by liver steatosis; inflammation and fibrosis are features of the progressive form nonalcoholic steatohepatitis. The endoplasmic reticulum stress response is postulated to play a role in the pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. In particular, C/EBP homologous protein (CHOP) is undetectable under normal conditions but is induced by cellular stress, including endoplasmic reticulum stress. Chop wild type (Chop+/+) and knock-out (Chop−/−) mice were used in these studies to elucidate the role of CHOP in the pathogenesis of fatty liver disease. Paradoxically, Chop−/− mice developed greater liver injury, inflammation, and fibrosis than Chop+/+ mice, with greater macrophage activation. Primary, bone marrow-derived, and peritoneal macrophages from Chop+/+ and Chop−/− were challenged with palmitic acid, an abundant saturated free fatty acid in plasma and liver lipids. Where palmitic acid treatment activated Chop+/+ and Chop−/− macrophages, Chop−/− macrophages were resistant to its lipotoxicity. Chop−/− mice were sensitized to liver injury in a second model of dietary steatohepatitis using the methionine-choline-deficient diet. Analysis of bone marrow chimeras between Chop−/− and Chop+/+ mice demonstrated that Chop in macrophages protects from liver injury and inflammation when fed the methionine-choline-deficient diet. We conclude that Chop deletion has a proinflammatory effect in fatty liver injury apparently due to decreased cell death of activated macrophages, resulting in their net accumulation in the liver. Thus, macrophage CHOP plays a key role in protecting the liver from steatohepatitis likely by limiting macrophage survival during lipotoxicity. Background: We hypothesized that C/EBP homologous protein mediates hepatocyte apoptosis in nonalcoholic steatohepatitis. Results: Paradoxically, Chop deletion protects from steatohepatitis by inducing apoptosis in activated macrophages. Conclusion: CHOP-dependent macrophage apoptosis in NASH highlights the cell type-specific complexity of the ER stress response. Significance: Therapeutic manipulation of mediators of ER stress response may have opposite effects in different cell populations; therefore, such studies should be interpreted cautiously.
- Published
- 2013
7. A Self-defeating Anabolic Program Leads to β-Cell Apoptosis in Endoplasmic Reticulum Stress-induced Diabetes via Regulation of Amino Acid Flux
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Jaeseok Han, Martin D. Snider, Elena Bevilacqua, Stefan Bröer, Randal J. Kaufman, Celvie L. Yuan, Marek Tchórzewski, Antonis E. Koromilas, Mridusmita Saikia, Ovidio Bussolati, Colleen M. Croniger, Michelle Puchowicz, Scot R. Kimball, Dawid Krokowski, Peter Arvan, Tao Pan, Mithu Majumder, Bo-Jhih Guan, and Maria Hatzoglou
- Subjects
Male ,Transcriptional Activation ,Amino Acid Transport Systems ,Cell Survival ,Eukaryotic Initiation Factor-2 ,Apoptosis ,Biology ,Biochemistry ,Amino Acyl-tRNA Synthetases ,Mice ,RNA, Transfer ,Insulin-Secreting Cells ,Protein biosynthesis ,Animals ,Humans ,Gene Regulation ,Chronic stress ,Amino acid transporter ,Amino Acids ,Phosphorylation ,Molecular Biology ,chemistry.chemical_classification ,Endoplasmic reticulum ,Cell Biology ,Endoplasmic Reticulum Stress ,Activating Transcription Factor 4 ,Cell biology ,Amino acid ,Mice, Inbred C57BL ,Glutamine ,HEK293 Cells ,Diabetes Mellitus, Type 2 ,chemistry ,Protein Biosynthesis ,Unfolded protein response ,Leucine ,Protein Processing, Post-Translational - Abstract
Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2α. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in β-cells in vivo. Paradoxically, chronic ER stress in β-cells induced an anabolic transcription program to overcome translational repression by eIF2α phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in β-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes.
- Published
- 2013
8. Exendin-4 inhibits glucolipotoxic ER stress in pancreatic β cells via regulation of SREBP1c and C/EBPβ transcription factors
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Yup Kang, Hee-Sook Jun, Jaeseok Han, Youn-Jung Lee, Oh-Kyung Lim, and Yoon Sin Oh
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endocrine system ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,MAPK8 ,Apoptosis ,Endocrinology ,Insulin-Secreting Cells ,Internal medicine ,medicine ,CEBPB ,Animals ,Gene knockdown ,Caspase 3 ,Venoms ,ATF6 ,Chemistry ,CCAAT-Enhancer-Binding Protein-beta ,Endoplasmic Reticulum Stress ,Rats ,Sterol regulatory element-binding protein ,ERN1 ,Unfolded protein response ,Exenatide ,Peptides ,Sterol Regulatory Element Binding Protein 1 - Abstract
Prolonged exposure to high glucose (HG) and palmitate (PA) results in increased ER stress and subsequently induces β-cell apoptosis. Exendin-4, a glucagon-like peptide-1 agonist, is known to protect β cells from toxicity induced by cytokines, HG, or fatty acids by reducing ER stress. However, the detailed molecular mechanisms for this protective effect are still not known. In this study, we investigated the role of exendin-4 in the inhibition of glucolipotoxicity-induced ER stress and β-cell apoptosis. Exendin-4 treatment protected INS-1 β cells from apoptosis in response to HG/PA (25 mM glucose+400 μM PA). HG/PA treatment increased cleaved caspase-3 and induced ER stress maker proteins such as PERK (EIF2AK3), ATF6, and phosphorylated forms of PERK, eIF2α, IRE1α (ERN1), and JNK (MAPK8), and these increases were significantly inhibited by exendin-4 treatment. HG/PA treatment of INS-1 cells increased SREBP1 (SREBF1) protein and induced its nuclear translocation and subsequently increased C/EBPβ (CEBPB) protein and its nuclear translocation. Exendin-4 treatment attenuated this increase. Knockdown ofSREBP1creduced the activation ofC/EBPβand also blocked the expression of ER stress markers induced by HG/PA treatment. Our results indicate that exendin-4 inhibits the activation of SREBP1c and C/EBPβ, which, in turn, may reduce glucolipotoxicity-induced ER stress and β-cell apoptosis.
- Published
- 2012
9. The role of ER stress in lipid metabolism and lipotoxicity
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Jaeseok Han and Randal J. Kaufman
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cell signaling ,Programmed cell death ,Apoptosis ,QD415-436 ,Biology ,Endoplasmic Reticulum ,Biochemistry ,lipids ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Organelle ,medicine ,cell signaling ,Animals ,Humans ,Muscle, Skeletal ,diabetes ,Endoplasmic reticulum ,Myocardium ,Lipid metabolism ,Thematic Review Series ,Cell Biology ,Endoplasmic Reticulum Stress ,Lipid Metabolism ,Cell biology ,030104 developmental biology ,Lipotoxicity ,Liver ,Unfolded protein response ,Unfolded Protein Response ,fatty acid ,030217 neurology & neurosurgery ,Homeostasis - Abstract
The endoplasmic reticulum (ER) is a cellular organelle important for regulating calcium homeostasis, lipid metabolism, protein synthesis, and posttranslational modification and trafficking. Numerous environmental, physiological, and pathological insults disturb ER homeostasis, referred to as ER stress, in which a collection of conserved intracellular signaling pathways, termed the unfolded protein response (UPR), are activated to maintain ER function for cell survival. However, excessive and/or prolonged UPR activation leads to initiation of self-destruction through apoptosis. Excessive accumulation of lipids and their intermediate products causes metabolic abnormalities and cell death, called lipotoxicity, in peripheral organs, including the pancreatic islets, liver, muscle, and heart. Because accumulating evidence links chronic ER stress and defects in UPR signaling to lipotoxicity in peripheral tissues, understanding the role of ER stress in cell physiology is a topic under intense investigation. In this review, we highlight recent findings that link ER stress and UPR signaling to the pathogenesis of peripheral organs due to lipotoxicity.
- Published
- 2016
10. The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation inβ‐cells
- Author
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Randal J. Kaufman, Justin R. Hassler, Jaeseok Han, Sung Hoon Back, and Benbo Song
- Subjects
PERK ,Male ,antioxidant ,Endocrinology, Diabetes and Metabolism ,eukaryotic initiation factor 2 ,translation ,Apoptosis ,Biology ,Endoplasmic Reticulum ,Diabetes Mellitus, Experimental ,Mice ,eIF-2 Kinase ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,protein folding ,Insulin-Secreting Cells ,Internal Medicine ,Protein biosynthesis ,Animals ,Humans ,ASK1 ,Secretion ,Review Articles ,030304 developmental biology ,Transcription Factor CHOP ,0303 health sciences ,EIF-2 kinase ,Endoplasmic reticulum ,Cell Differentiation ,3. Good health ,Cell biology ,mitochondria ,Mice, Inbred C57BL ,Oxidative Stress ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Biochemistry ,Protein Biosynthesis ,Unfolded Protein Response ,biology.protein ,Unfolded protein response ,Phosphorylation ,CHOP ,030217 neurology & neurosurgery - Abstract
Diabetes is an epidemic of worldwide proportions caused by β-cell failure. Nutrient fluctuations and insulin resistance drive β-cells to synthesize insulin beyond their capacity for protein folding and secretion and thereby activate the unfolded protein response (UPR), an adaptive signalling pathway to promote cell survival upon accumulation of unfolded protein in the endoplasmic reticulum (ER). Protein kinase-like endoplasmic reticulum kinase (PERK) signals one component of the UPR through phosphorylation of eukaryotic initiation factor 2 on the α-subunit (eIF2α) to attenuate protein synthesis, thereby reducing the biosynthetic burden. β-Cells uniquely require PERK-mediated phosphorylation of eIF2α to preserve cell function. Unabated protein synthesis in β-cells is sufficient to initiate a cascade of events, including oxidative stress, that are characteristic of β-cell failure observed in type 2 diabetes. In contrast to acute adaptive UPR activation, chronic activation increases expression of the proapoptotic transcription factor CAAT/enhancer-binding protein homologous protein (CHOP). Chop deletion in insulin-resistant mice profoundly increases β-cell mass and prevents β-cell failure to forestall the progression of diabetes. The findings suggest an unprecedented link by which protein synthesis and/or misfolding in the ER causes oxidative stress and should encourage the development of novel strategies to treat diabetes.
- Published
- 2010
11. Gamma Interferon Paradoxically Inhibits the Development of Diabetes in the NOD Mouse
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Behrouz Ahvazi, Joy A. Williams, Douglas O. Sobel, Jaeseok Han, Ji-Won Yoon, and Hee-Sook Jun
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medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Genes, MHC Class I ,Apoptosis ,Spleen ,Biology ,medicine.disease_cause ,Autoimmunity ,Interferon-gamma ,Islets of Langerhans ,Mice ,Antigens, CD ,Mice, Inbred NOD ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Immunology and Allergy ,Interferon gamma ,NOD mice ,geography ,Membrane Glycoproteins ,geography.geographical_feature_category ,Islet ,medicine.disease ,medicine.anatomical_structure ,Cytokine ,Endocrinology ,B7-1 Antigen ,Cytokines ,Female ,B7-2 Antigen ,Cell Adhesion Molecules ,Insulitis ,medicine.drug - Abstract
Gamma interferon (IFN-gamma) has been thought to play an important role in the pathogenesis of diabetes. This report determines if rIFN-gamma administration to NOD mice paradoxically inhibits the development of diabetes. Injections of recombinant rIFN-gamma of 5 x 10(3), 20 x 10(3), and 100 x 10(3) units, dose dependently inhibited the development of diabetes. The maximal rIFN-gamma dose decreased the incidence of diabetes from 74% in control animals to 42%. 100x10(3) unit rIFN-gamma dose significantly decreased insulitis score, and increased islet number. The development of diabetes in irradiated NOD mice was slower in animals injected with spleen cells from rIFN-gamma treated than from saline treated NOD mice suggesting that rIFN-gamma decreases anti-islet effector cell activity. The susceptibility to apoptosis was increased in splenic cells of rIFN-gamma treated mice. The expressions of the co-stimulatory molecules B7-2 and ICAM-1 were significantly increased in spleen cells of rIFN-gamma treated mice while the expression of MHC class I was decreased. In vitro studies demonstrated that NOD mouse mononuclear spleen cells preincubated with rIFN-gamma and subsequently cocultured with responder cells, potently inhibited responder T-cell proliferative responses. rIFN-gamma administration decreased IL-12 and IL-2 mRNA expression in spleen cells while increasing IL-1 expression. In conclusion, rIFN-gamma inhibits the diabetic process in NOD mice by decreasing anti-islet effector activity and in turn decreasing insulitis and islet destruction. The suppression of Th1 cell related cytokines and/or augmentation of the macrophage cytokine IL-1 may play a role in the diabetes sparing effect of rIFN-gamma.
- Published
- 2002
12. Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress-induced cell death during the unfolded protein response
- Author
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Nobuhiko Hiramatsu, Matthew M. LaVail, Randal J. Kaufman, Carissa Messah, Jonathan H. Lin, Jaeseok Han, and Gilmore, Reid
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Programmed cell death ,endocrine system ,Cell Survival ,Eukaryotic Initiation Factor-2 ,Messenger ,Down-Regulation ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Biology ,CHOP ,Medical and Health Sciences ,Cell Line ,eIF-2 Kinase ,Downregulation and upregulation ,Enhancer binding ,Cell Line, Tumor ,Genetics ,2.1 Biological and endogenous factors ,Animals ,Humans ,RNA, Messenger ,Aetiology ,Molecular Biology ,Protein Processing ,Tumor ,Endoplasmic reticulum ,Post-Translational ,Cell Biology ,Articles ,Biological Sciences ,Endoplasmic Reticulum Stress ,Activating Transcription Factor 4 ,3. Good health ,Cell biology ,XIAP ,HEK293 Cells ,Cell Biology of Disease ,Protein Biosynthesis ,Proteolysis ,Cancer research ,Unfolded protein response ,Unfolded Protein Response ,RNA ,Generic health relevance ,Protein Processing, Post-Translational ,Transcription Factor CHOP ,Developmental Biology - Abstract
Chronic ER stress down-regulates XIAP by activating the PERK branch of the UPR. PERK attenuates Xiap translation via eIF2α phosphorylation. PERK promotes XIAP degradation via ATF4. CHOP induction and XIAP suppression act in parallel to sensitize cells to ER stress–induced apoptosis., Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.
- Published
- 2014
13. Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2
- Author
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Eric Lau, Ze'ev Ronai, Laurence M. Brill, Jian-Liang Li, Marzia Scortegagna, David D.L. Bowtell, Hang Yao, Hyungsoo Kim, Gabriel G. Haddad, Jaeseok Han, and Randal J. Kaufman
- Subjects
Cancer Research ,Transcription, Genetic ,Endoplasmic Reticulum ,Biochemistry ,Mice ,Signal Initiation ,Cell Signaling ,Ubiquitin ,Cricetinae ,Molecular Cell Biology ,Medicine and Health Sciences ,Cells, Cultured ,Genetics (clinical) ,Cellular Stress Responses ,Cell Death ,biology ,Mechanisms of Signal Transduction ,Signaling Cascades ,Isoenzymes ,Cell Processes ,Intracellular ,Research Article ,Signal Transduction ,Programmed cell death ,Feedback Regulation ,lcsh:QH426-470 ,Ubiquitin-Protein Ligases ,CHO Cells ,Real-Time Polymerase Chain Reaction ,Research and Analysis Methods ,Stress Signaling Cascade ,Cricetulus ,Model Organisms ,Stress, Physiological ,Genetics ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Endoplasmic reticulum ,ATF4 ,Wild type ,Biology and Life Sciences ,Cell Biology ,Molecular biology ,Enzyme Activation ,lcsh:Genetics ,Apoptosis ,Unfolded Protein Response ,biology.protein ,Unfolded protein response ,Transcriptional Signaling - Abstract
The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a+/−::Siah2−/− mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions., Author Summary Maintaining a balanced level of stress (protein folding, reactive oxygen radicals) is important for keeping cellular homeostasis (the ability of a cell to maintain internal equilibrium by adjusting its physiological processes). The accumulation of stress (external or internal) will trigger a well-orchestrated machinery that attempts to restore homeostasis, namely, the unfolded protein response (UPR). The UPR either restores balance to the cells or induces a cell death program, which clears the damaged cell. How this machinery activates cell survival versus cell death is not entirely clear. Here we identify a new layer in the regulation of the UPR, which determines the magnitude of this response. We demonstrate the importance of this newly identified regulatory component for cell death commitments, in response to the more severe conditions (ischemia, lack of oxygen and nutrients). Our findings highlight an undisclosed mechanism that is important for the cell death decision following severe stress conditions, while pointing to the ability to fine tune cellular response to stress.
- Published
- 2014
14. Selective transcriptional regulations in the human liver cell by hepatitis B viral X protein
- Author
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Jaeseok Han, Hae Yong Yoo, Byung Hyune Choi, and Hyune Mo Rho
- Subjects
Hepatitis B virus ,DNA, Complementary ,Response element ,Biophysics ,Apoptosis ,Biology ,Transfection ,Biochemistry ,Sp3 transcription factor ,Genes, Reporter ,Tumor Cells, Cultured ,E2F1 ,Humans ,Genes, Tumor Suppressor ,Viral Regulatory and Accessory Proteins ,RNA, Messenger ,Growth Substances ,Molecular Biology ,Transcription factor ,beta Catenin ,Oligonucleotide Array Sequence Analysis ,General transcription factor ,Gene Expression Profiling ,Promoter ,Cell Biology ,TCF4 ,Oncogenes ,Intercellular Adhesion Molecule-1 ,Molecular biology ,digestive system diseases ,Genes, cdc ,HBx ,Cytoskeletal Proteins ,Gene Expression Regulation ,Liver ,Trans-Activators ,Signal Transduction - Abstract
The hepatitis B viral X protein (HBx) is known as a transcription factor and potential oncogene. To gain a better view of the effect of HBx on the transcriptional regulation in the human liver cell, we constructed a HepG2 cell line stably expressing HBx (HepG2-HBx), and performed cDNA microarray analysis on 588 cellular cDNAs comparing with untransformed control cells. Two genes (IGFR-2, RhoA) of oncogenes, one gene (p55CDC) of cell cycle regulators, three genes (thrombin receptor, MLK-3, MacMARCKS) of intracellular transducers, one gene (HSP27) of stress response proteins, two genes (FAST kinase, Bak) of apoptosis response proteins, one gene (p21 WAF ) of transcription factors were highly up-regulated; one gene (transcription elongation factor SII) of transcription factors and two genes (monocyte chemotactic protein 1, T-lymphocyte-secreted protein I-309) of growth factors were highly down-regulated. These results showed selective transcriptional regulation by HBx in the human liver cell.
- Published
- 2000
15. Endoplasmic Reticulum Stress in the β-Cell Pathogenesis of Type 2 Diabetes.
- Author
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Sung Hoon Back, Sang-Wook Kang, Jaeseok Han, and Hun-Taeg Chung
- Subjects
METABOLIC disorders ,TYPE 2 diabetes ,ENDOPLASMIC reticulum ,BLOOD sugar ,INSULIN resistance ,APOPTOSIS ,CELL death - Abstract
Type 2 diabetes is a complex metabolic disorder characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency by β-cell failure. Even if the mechanisms underlying the pathogenesis of β-cell failure are still under investigation, recent increasing genetic, experimental, and clinical evidence indicate that hyperactivation of the unfolded protein response (UPR) to counteract metabolic stresses is closely related to β-cell dysfunction and apoptosis. Signaling pathways of the UPR are "a double-edged sword" that can promote adaptation or apoptosis depending on the nature of the ER stress condition. In this paper, we summarized our current understanding of the mechanisms and components related to ER stress in the β-cell pathogenesis of type 2 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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