Chemotherapy: induction of stress responses

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S115-S124 ◽  
Author(s):  
E Tiligada
Keyword(s):  
Anticancer Agents ◽  
Stress Responses ◽  
Chemotherapeutic Agents ◽  
Clinical Value ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Shock Proteins ◽  
And Function ◽  
Protein Response ◽  
Functional Components

Eukaryotic cells, from yeast to mammals, respond and adapt to environmental and microenvironmental stressors by evolutionary conserved multicomponent endogenous systems that utilise a network of signal transduction pathways to regulate the adaptive and protective phenotype. The balance between cell survival and cell death is decisive for sensitivity or resistance to DNA-damaging chemotherapeutic agents. Anticancer drugs may themselves act as stressors to induce adaptive signals that could limit their clinical value. Related research has been focused on the modulation of the expression and function of the heat shock proteins, the unfolded protein response, the mechanisms of subcellular translocation of signalling components, the genomic and non-genomic actions of drugs and endogenous functional components like hormonal pathways, the input of inflammation and alterations in the microenvironmental milieu and on the control of the cell cycle and proliferation. The outcome seems to be driven by the first-line responses that support cellular integrity and by specific mechanisms that depend on the type of cell and the nature, and duration and severity of the noxious stimulus. Data obtained from experimental organisms like the yeast have added valuable information on the basic conservation in cellular stress-related processes in eukaryotes and on the consequences that may accompany the adaptive and protective phenotype during the stress response to anticancer agents. Understanding the complex molecular pathways mediating these processes has started to contribute to the reevaluation of the current therapeutic regiments and to revolutionise the approaches for improved anticancer therapy.

scholarly journals Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

2019 ◽  
Vol 20 (7) ◽  
pp. 1792 ◽  
Author(s):  
Kyeorda Kemp ◽  
Cody Poe
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
Unfolded Protein Response ◽  
T Cell Development ◽  
Cell Development ◽  
Secretory Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

scholarly journals Herpesviruses and the Unfolded Protein Response

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 17 ◽  
Author(s):  
Benjamin P. Johnston ◽  
Craig McCormick
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Immune Surveillance ◽  
Lytic Replication ◽  
Glycoprotein Synthesis ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Molecular Events ◽  
The Unfolded Protein Response ◽  
Protein Response

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

scholarly journals Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

2019 ◽  
Vol 5 (4) ◽  
pp. eaaw0025 ◽  
Author(s):  
Milos S. Simic ◽  
Erica A. Moehle ◽  
Robert T. Schinzel ◽  
Franziska K. Lorbeer ◽  
Jonathan J. Halloran ◽  
...  
Keyword(s):  
Cellular Reprogramming ◽  
Epigenetic Landscape ◽  
Form And Function ◽  
Unfolded Protein ◽  
Transient Activation ◽  
Reprogramming Efficiency ◽  
Low Efficiency ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

Somatic cells can be reprogrammed into pluripotent stem cells using the Yamanaka transcription factors. Reprogramming requires both epigenetic landscape reshaping and global remodeling of cell identity, structure, basic metabolic processes, and organelle form and function. We hypothesize that variable regulation of the proteostasis network and its influence upon the protein-folding environment within cells and their organelles is responsible for the low efficiency and stochasticity of reprogramming. We find that the unfolded protein response of the endoplasmic reticulum (UPRER), the mitochondrial UPR, and the heat shock response, which ensure proteome quality during stress, are activated during reprogramming. The UPRER is particularly crucial, and its ectopic, transient activation, genetically or pharmacologically, enhances reprogramming. Last, stochastic activation of the UPRER predicts reprogramming efficiency in naïve cells. Thus, the low efficiency and stochasticity of cellular reprogramming are due partly to the inability to properly initiate the UPRER to remodel the ER and its proteome.

scholarly journals The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily M. Nakada ◽  
Rui Sun ◽  
Utako Fujii ◽  
James G. Martin
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Lung Structure ◽  
Selective Translation ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

scholarly journals GAS1Deficient Enhances UPR Activity inSaccharomyces cerevisiae

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Hong-jing Cui ◽  
Xin-gang Cui ◽  
Xia Jing ◽  
Yuan Yuan ◽  
Ya-qin Chen ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Yeast Cells ◽  
Unfolded Protein ◽  
Proliferation Ability ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cycle Regulation ◽  
Wild Type Yeast

Beta-1,3-glucanosyltransferase (Gas1p) plays important roles in cell wall biosynthesis and morphogenesis and has been implicated in DNA damage responses and cell cycle regulation in fungi. Yeast Gas1p has also been reported to participate in endoplasmic reticulum (ER) stress responses. However, the precise roles and molecular mechanisms through which Gas1p affects these responses have yet to be elucidated. In this study, we constructedGAS1-deficient (gas1Δ) andGAS1-overexpressing (GAS1 OE) yeast strains and observed that thegas1Δstrain exhibited a decreased proliferation ability and a shorter replicative lifespan (RLS), as well as enhanced activity of the unfolded protein response (UPR) in the absence of stress. However, under the high-tunicamycin-concentration (an ER stress-inducing agent; 1.0 μg/mL) stress, thegas1Δyeast cells exhibited an increased proliferation ability compared with the wild-type yeast strain. In addition, our findings demonstrated thatIRE1andHAC1(two upstream modulators of the UPR) are required for the survival ofgas1Δyeast cells under the tunicamycin stress. On the other hand, we provided evidence that theGAS1overexpression caused an obvious sensitivity to the low-tunicamycin-concentration (0.25 μg/mL). Collectively, our results indicate that Gas1p plays an important role in the ageing and ER stress responses in yeast.

Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

2020 ◽  
Vol 39 (12) ◽  
pp. 1690-1699
Author(s):  
H Yu ◽  
K Wen ◽  
X Zhou ◽  
Y Zhang ◽  
Z Yan ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Messenger Rna ◽  
Hypoxia Inducible Factor ◽  
Reproductive Organs ◽  
Pregnant Mouse ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

scholarly journals Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

2019 ◽  
Vol 71 (5) ◽  
pp. 1659-1667 ◽  
Author(s):  
Taiaba Afrin ◽  
Danish Diwan ◽  
Katrina Sahawneh ◽  
Karolina Pajerowska-Mukhtar
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Translational Control ◽  
Protein Quality ◽  
Unfolded Protein ◽  
Transcriptional Gene Regulation ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

scholarly journals ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

2020 ◽  
Author(s):  
Emma Louise Wilson ◽  
Emmanouil Metzakopian
Keyword(s):  
Neurodegenerative Diseases ◽  
High Throughput Screening ◽  
Current Knowledge ◽  
Unfolded Protein ◽  
Advantages And Disadvantages ◽  
Contact Sites ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Related Proteins

AbstractMitochondria-ER contact sites (MERCS) are known to underpin many important cellular homoeostatic functions, including mitochondrial quality control, lipid metabolism, calcium homoeostasis, the unfolded protein response and ER stress. These functions are known to be dysregulated in neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD) and amyloid lateral sclerosis (ALS), and the number of disease-related proteins and genes being associated with MERCS is increasing. However, many details regarding MERCS and their role in neurodegenerative diseases remain unknown. In this review, we aim to summarise the current knowledge regarding the structure and function of MERCS, and to update the field on current research in PD, AD and ALS. Furthermore, we will evaluate high-throughput screening techniques, including RNAi vs CRISPR/Cas9, pooled vs arrayed formats and how these could be combined with current techniques to visualise MERCS. We will consider the advantages and disadvantages of each technique and how it can be utilised to uncover novel protein pathways involved in MERCS dysfunction in neurodegenerative diseases.

scholarly journals ER homeostasis and autophagy

2017 ◽  
Vol 61 (6) ◽  
pp. 625-635 ◽  
Author(s):  
Matthew Smith ◽  
Simon Wilkinson
Keyword(s):  
Secretory Proteins ◽  
Unfolded Protein ◽  
Effector Pathway ◽  
Autophagy Pathway ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
Effector Mechanisms

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

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