Cell Pathology最新文献

{"title":"The unfolded protein response, inflammation, oscillators, and disease: a systems biology approach","authors":"R. Rangel‐Aldao","doi":"10.1515/ersc-2015-0003","DOIUrl":"https://doi.org/10.1515/ersc-2015-0003","url":null,"abstract":"Abstract Non-communicable diseases (NCDs) such as cardiovascular disease, cancers, diabetes and obesity are responsible for about two thirds of mortality worldwide, and all of these ailments share a common low-intensity systemic chronic inflammation, endoplasmic reticulum stress (ER stress), and the ensuing Unfolded Protein Response (UPR). These adaptive mechanisms are also responsible for significant metabolic changes that feedback with the central clock of the suprachiasmatic nucleus (SCN) of the hypothalamus, as well as with oscillators of peripheral tissues. In this review we attempt to use a systems biology approach to explore such interactions as a whole; to answer two fundamental questions: (1) how dependent are these adaptive responses and subsequent events leading to NCD with their state of synchrony with the SCN and peripheral oscillators? And, (2) How could modifiers of the activity of SCN for instance, food intake, exercise, and drugs, be potentially used to modulate systemic inflammation and ER stress to ameliorate or even prevent NCDs?","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90983611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of kinase and endoribonuclease activity of ERN1/IRE1α affects expression of proliferation related genes in U87 glioma cells","authors":"O. Minchenko, D. O. Tsymbal, D. Minchenko, M. Moenner, O. V. Kovalevska, N. M. Lypova","doi":"10.1515/ersc-2015-0002","DOIUrl":"https://doi.org/10.1515/ersc-2015-0002","url":null,"abstract":"Abstract Inhibition of ERN1/IRE1α (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme-1α), the major signaling pathway of endoplasmic reticulum stress, significantly decreases tumor growth. We have studied the expression of transcription factors such as E2F8 (E2F transcription factor 8), EPAS1 (endothelial PAS domain protein 1), TBX3 (T-box 3), ATF3 (activating transcription factor 3), FOXF1 (forkhead box F1), and HOXC6 (homeobox C6) in U87 glioma cells overexpressing dominant-negative ERN1/IRE1α defective in endoribonuclease (dnr-ERN1) as well as defective in both kinase and endonuclease (dn-ERN1) activity of ERN1/IRE1α. We have demonstrated that the expression of all studied genes is decreased at the mRNA level in cells with modified ERN1/IRE1α; TBX3, however, is increased in these cells as compared to control glioma cells. Changes in protein levels of E2F8, HOXC6, ATF3, and TBX3 corresponded to changes in mRNAs levels. We also found that two mutated ERN1/IRE1α have differential effects on the expression of studied transcripts. The presence of kinase and endonuclease deficient ERN1/IRE1α in glioma cells had a less profound effect on the expression of E2F8, HOXC6, and TBX3 genes than the blockade of the endoribonuclease activity of ERN1/IRE1α alone. Kinase and endonuclease deficient ERN1/IRE1α suppresses ATF3 and FOXF1 gene expressions, while inhibition of only endoribonuclease of ERN1/IRE1α leads to the up-regulation of these gene transcripts. The present study demonstrates that fine-tuning of the expression of proliferation related genes is regulated by ERN1/IRE1α an effector of endoplasmic reticulum stress. Inhibition of ERN1/IRE1α, especially its endoribonuclease activity, correlates with deregulation of proliferation related genes and thus slower tumor growth.","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91311419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease","authors":"Toru Hosoi, J. Nomura, K. Ozawa, A. Nishi, Y. Nomura","doi":"10.1515/ersc-2015-0008","DOIUrl":"https://doi.org/10.1515/ersc-2015-0008","url":null,"abstract":"Abstract The endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80979132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From recordings of disulfide isomerases in action to reversal of maladaptive endoplasmic reticulum stress responses: proceedings on the ER & Redox Club Meeting held in Venice, April 2015","authors":"E. van Anken","doi":"10.1515/ersc-2015-0006","DOIUrl":"https://doi.org/10.1515/ersc-2015-0006","url":null,"abstract":"Abstract The endoplasmic reticulum (ER) interacts and cooperates with other organelles as a central hub in cellular homeostasis. In particular, the ER is the first station along the secretory pathway, where client proteins fold and assemble before they travel to their final destination elsewhere in the endomembrane system or outside the cell. Protein folding and disulfide bond formation go hand in hand in the ER, a task that is achieved with the help of ER-resident chaperones and other folding factors, including oxidoreductases that catalyze disulfide bond formation. Yet, when their combined effort is in vain, client proteins that fail to fold are disposed of through ER-associated degradation (ERAD). The ER folding and ERAD machineries can be boosted through the unfolded protein response (UPR) if required. Still, protein folding in the ER may consistently fail when proteins are mutated due to a genetic defect, which, ultimately, can lead to disease. Novel developments in all these fields of study and how new insights ultimately can be exploited for clinical or biotechnological purposes were highlighted in a rich variety of presentations at the ER & Redox Club Meeting that was held in Venice from 15 to 17 April 2015. As such, the meeting provided the participants an excellent opportunity to mingle and discuss key advancements and outstanding questions on ER function in health and disease.","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91065788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Saturated fatty acids induce endoplasmic reticulum stress in primary cardiomyocytes","authors":"T. Haffar, Félix-Antoine Bérubé-Simard, J. Tardif, N. Bousette","doi":"10.1515/ersc-2015-0004","DOIUrl":"https://doi.org/10.1515/ersc-2015-0004","url":null,"abstract":"Abstract Abstract: Introduction: Diabetes is a major contributor to cardiovascular disease. There is a growing body of evidence pointing towards intra-myocellular lipid accumulation as an integral etiological factor. Here we aimed to determine the effect of two common fatty acids on lipid accumulation and cellular stress in primary cardiomyocytes. Methods: We evaluated lipid accumulation biochemically (by triacylglyceride assay and radiolabeled fatty acid uptake assay) as well as histologically (by BODIPY 493/503 staining) in mouse and rat neonatal cardiomyocytes treated with saturated (palmitate) or mono-unsaturated (oleate) fatty acids. Endoplasmic reticulum (ER) stress was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability was assessed by propidium iodide staining. Results: We found that both oleate and palmitate led to significant increases in intracellular lipid in cardiomyocytes; however there were distinct differences in the qualitative nature of BODIPY staining between oleate and palmitate treated cardiomyocytes. We also show that palmitate caused significant apoptotic cell death and this was associated with ER stress. Interestingly, co-administration of oleate with palmitate abolished cell death, and ER stress. Finally, palmitate treatment caused a significant increase in ubiquitination of Grp78, a key compensatory ER chaperone. Conclusion: Palmitate causes ER stress and apoptotic cell death in primary cardiomyocytes and this is associated with apparent differences in BODIPY staining compared to oleate treated cardiomyocytes. Importantly, the lipotoxic effects of palmitate are abolished with the co-administration of oleate.","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90896881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Approaches to imaging unfolded secretory protein stress in living cells.","authors":"Patrick Lajoie,&nbsp;Elena N Fazio,&nbsp;Erik L Snapp","doi":"10.2478/ersc-2014-0002","DOIUrl":"https://doi.org/10.2478/ersc-2014-0002","url":null,"abstract":"<p><p>The endoplasmic reticulum (ER) is the point of entry of proteins into the secretory pathway. Nascent peptides interact with the ER quality control machinery that ensures correct folding of the nascent proteins. Failure to properly fold proteins can lead to loss of protein function and cytotoxic aggregation of misfolded proteins that can lead to cell death. To cope with increases in the ER unfolded secretory protein burden, cells have evolved the Unfolded Protein Response (UPR). The UPR is the primary signaling pathway that monitors the state of the ER folding environment. When the unfolded protein burden overwhelms the capacity of the ER quality control machinery, a state termed ER stress, sensor proteins detect accumulation of misfolded peptides and trigger the UPR transcriptional response. The UPR, which is conserved from yeast to mammals, consists of an ensemble of complex signaling pathways that aims at adapting the ER to the new misfolded protein load. To determine how different factors impact the ER folding environment, various tools and assays have been developed. In this review, we discuss recent advances in live cell imaging reporters and model systems that enable researchers to monitor changes in the unfolded secretory protein burden and activation of the UPR and its associated signaling pathways.</p>","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2478/ersc-2014-0002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32833051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis.","authors":"C Grek, D M Townsend","doi":"10.2478/ersc-2013-0001","DOIUrl":"10.2478/ersc-2013-0001","url":null,"abstract":"<p><p>Cellular homeostasis requires the balance of a multitude of signaling cascades that are contingent upon the essential proteins being properly synthesized, folded and delivered to appropriate subcellular locations. In eukaryotic cells the endoplasmic reticulum (ER) is a specialized organelle that is the central site of synthesis and folding of secretory, membrane and a number of organelletargeted proteins. The integrity of protein folding is enabled by the presence of ATP, Ca⁺⁺, molecular chaperones, as well as an oxidizing redox environment. The imbalance between the load and capacity of protein folding results in a cellular condition known as ER stress. Failure of these pathways to restore ER homeostasis results in the activation of apoptotic pathways. Protein disulfide isomerases (PDI) compose a superfamily of oxidoreductases that have diverse sequences and are localized in the ER, nucleus, cytosol, mitochondria and cell membrane. The PDI superfamily has multiple functions including, acting as molecular chaperones, protein-binding partners, and hormone reservoirs. Recently, PDI family members have been implicated in the regulation of apoptotic signaling events. The complexities underlying the molecular mechanisms that define the switch from pro-survival to pro-death response are evidenced by recent studies that reveal the roles of specific chaperone proteins as integration points in signaling pathways that determine cell fate. The following review discusses the dual role of PDI in cell death and survival during ER stress.</p>","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192724/pdf/nihms597755.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32741623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of ERN1 modifies the hypoxic regulation of the expression of TP53-related genes in U87 glioma cells","authors":"D. Minchenko, S. V. Danilovskyi, I. V. Kryvdiuk, T. V. Bakalets, N. M. Lypova, L. L. Karbovskyi, O. Minchenko","doi":"10.2478/ersc-2014-0001","DOIUrl":"https://doi.org/10.2478/ersc-2014-0001","url":null,"abstract":"Abstract Inhibition of ERN1 (endoplasmic reticulum to nuclei 1), the major signalling pathway of endoplasmic reticulum stress, significantly decreases tumor growth. We have studied the expression of tumor protein 53 (TP53)- related genes such as TOPORS (topoisomerase I binding, arginine/serine-rich, E3 ubiquitin protein ligase), TP53BP1 (TP53 binding protein 1), TP53BP2, SESN1 (sestrin 1), NME6 (non-metastatic cells 6), and ZMAT3 (zinc finger, Matrin-type 3) in glioma cells expressing dominantnegative ERN1 under baseline and hypoxic conditions. We demonstrated that inhibition of ERN1 function in U87 glioma cells resulted in increased expression of RYBP, TP53BP2, and SESN1 genes, but decreased expression of TP53BP1, TOPORS, NME6, and ZMAT3 genes. Moreover, inhibition of ERN1 affected hypoxia-mediated changes in expression of TP53-related genes and their magnitude. Indeed, hypoxia has no effect on expression of TP53BP1 and SESN1 in control cells, while resulted in increased expression of these genes in cells with inhibited ERN1 function. Magnitude of hypoxia-mediated changes in expression levels of RYBP and TP53BP2 was gene specific and more robust in the case of TP53BP2. Hypoxiamediated decrease in expression levels of TOPORS was more prominent if ERN1 was inhibited. Present study demonstrates that fine-tuning of the expression of TP53- associated genes depends upon endoplasmic reticulum stress signaling under normal and hypoxic conditions. Inhibition of ERN1 branch of endoplasmic reticulum stress response correlates with deregulation of p53 signaling and slower tumor growth.","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90974466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1","authors":"Danilo Swann Matassa, Diana Arzeni, M. Landriscina, F. Esposito","doi":"10.2478/ersc-2014-0003","DOIUrl":"https://doi.org/10.2478/ersc-2014-0003","url":null,"abstract":"Abstract TRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles’ homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82762834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic Reticulum Stress Response, the Future of Cancer Research and a New Designated Journal","authors":"A. Blumental-Perry","doi":"10.2478/ersc-2012-0001","DOIUrl":"https://doi.org/10.2478/ersc-2012-0001","url":null,"abstract":"The Endoplasmic Reticulum Stress Response (ERSR), the understanding of its mechanisms, and its contribution to the numerous vital functions of the cell are both the most avantgarde and highest priority in basic and clinical biomedical research fields. Like many other important fields in biology, ERSR started completely as basic research, with the most important discoveries made in yeast, immunoglobulin assembly and metabolic cellular studies [1,2]. Protein chaperones, such as Grp78 and Grp94, were indeed discovered in glucose starvation experiments between the mid-seventies and eighties by Pastan’s lab [3]. Gething and Sambrook understood the importance of chaperone up-regulation and discovered common elements in their promoters that govern chaperones’ transcriptional control. It was in 1992 when the term “Unfolded Protein Response” (UPR) was first used [4]. The yeast IRE1 trans-membrane kinase and ribonuclease was the first sensor of the accumulation of unfolded proteins in ER cloned in 1998 by two labs, Sambrook and Walter [5,6]. IRE1 is the most evolutionary conserved branch of UPR and the only one present in yeast. The rescue of IRE1 -/yeast cells by over-expression of Hac1p transcription factor revealed the unique mode of action of IREα ref., thus connecting the sensing of ERS and the massive transcriptional program initiated by UPR signaling. Beautifully surprising and somehow expected is the story of mammalian UPR sensors’ identification [7-11]. As compared to that of the yeast, the mammalian system shows much more complexity and redundancy due to contributions from at least 3 major pathways of UPR: IRE1α and IREα, PERK and ATF6. PERK added extra release to the stressed ER by translational attenuation of new protein synthesis. Before XBP1 was identified and connected to UPR, it was thought that ATF6 fulfilled Hac1 function in higher eukaryotes [12,13]. Slowly, the primary components of UPR have been unveiled; experiments implementing “classical” and artificial UPR inducers, such as Tunicamycin and Thapsigargin, have helped to delineate the core mechanisms of UPR induction as well as Endoplasmic Reticulum Stress Response, the Future of Cancer Research and a New Designated Journal. Editorial • DOI: 10.2478/ersc-2012-0001 • ERSC • 201 • 1-3","PeriodicalId":29730,"journal":{"name":"Cell Pathology","volume":null,"pages":null},"PeriodicalIF":0.7,"publicationDate":"2012-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76933652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}