Special Issue "Cellular Stress Response"

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 July 2012)

Special Issue Editor

Guest Editor
Dr. Alex Almasan (Website)

Department of Cancer Biology, Bridge appointment with Department of Radiation Oncology, Taussig Cancer Institute, Lerner Research Institute / NB40, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Phone: 216-444-9970
Interests: apoptosis; autophagy; cancer (leukemia and prostate); cell death; cell cycle; DNA damage and repair

Special Issue Information

Dear Colleagues,

Cells are constantly subjected to various forms of endogenous and exogenous stress that shapes their existence. How they respond to it depends on exogenous factors and their ability to handle the stress to which they are exposed.   Examples of cellular stress are the DNA damage caused by radiation, chemotherapy, hypoxia, oncogene activation; these will ultimately lead to transient or permanent (senescence) growth arrest, or if the damage is severe, death that ultimately eliminates the damaged cells . Whether cells mount a protective response or succumb to death depends to a large extent on the nature and duration of the stress and the particular cell type. How such cellular stress leads to activation of pro-survival molecules that may activate repair of DNA damage in the nucleus or in the cytoplasm by autophagy (see dedicated special issue) and/or prevent cell death is of considerable interest. Moreover, alternative splicing and the adaptive response are of special interest.

This Special Issue offers an Open Access forum that aims at bringing together a collection of original research and review articles addressing recent developments in the cellular stress response, the signaling pathways that mitigate its biological effects and the ensuing cell proliferation and/or survival outcomes.

Dr. Alex Almasan
Guest Editor

Keywords

  • Adaptation
  • Autophagy
  • Cell cycle arrest
  • Cellular stress
  • DNA repair
  • Genotoxic stress
  • Hypoxia
  • Oncogene activation
  • Oxidative stress
  • Programmed cell death
  • Senescence

Published Papers (11 papers)

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Research

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Open AccessArticle Temporal Gene Expression Kinetics for Human Keratinocytes Exposed to Hyperthermic Stress
Cells 2013, 2(2), 224-243; doi:10.3390/cells2020224
Received: 28 February 2013 / Revised: 29 March 2013 / Accepted: 2 April 2013 / Published: 10 April 2013
Cited by 1 | PDF Full-text (1460 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The gene expression kinetics for human cells exposed to hyperthermic stress are not well characterized. In this study, we identified and characterized the genes that are differentially expressed in human epidermal keratinocyte (HEK) cells exposed to hyperthermic stress. In order to obtain [...] Read more.
The gene expression kinetics for human cells exposed to hyperthermic stress are not well characterized. In this study, we identified and characterized the genes that are differentially expressed in human epidermal keratinocyte (HEK) cells exposed to hyperthermic stress. In order to obtain temporal gene expression kinetics, we exposed HEK cells to a heat stress protocol (44 °C for 40 min) and used messenger RNA (mRNA) microarrays at 0 h, 4 h and 24 h post-exposure. Bioinformatics software was employed to characterize the chief biological processes and canonical pathways associated with these heat stress genes. The data shows that the genes encoding for heat shock proteins (HSPs) that function to prevent further protein denaturation and aggregation, such as HSP40, HSP70 and HSP105, exhibit maximal expression immediately after exposure to hyperthermic stress. In contrast, the smaller HSPs, such as HSP10 and HSP27, which function in mitochondrial protein biogenesis and cellular adaptation, exhibit maximal expression during the “recovery phase”, roughly 24 h post-exposure. These data suggest that the temporal expression kinetics for each particular HSP appears to correlate with the cellular function that is required at each time point. In summary, these data provide additional insight regarding the expression kinetics of genes that are triggered in HEK cells exposed to hyperthermic stress. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Open AccessArticle Cellular Stress Following Water Deprivation in the Model Legume Lotus japonicus
Cells 2012, 1(4), 1089-1106; doi:10.3390/cells1041089
Received: 1 August 2012 / Revised: 9 November 2012 / Accepted: 9 November 2012 / Published: 13 November 2012
Cited by 4 | PDF Full-text (382 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Drought stress is one of the most important factors in the limitation of plant productivity worldwide. In order to cope with water deprivation, plants have adopted several strategies that produce major changes in gene expression. In this paper, the response to drought [...] Read more.
Drought stress is one of the most important factors in the limitation of plant productivity worldwide. In order to cope with water deprivation, plants have adopted several strategies that produce major changes in gene expression. In this paper, the response to drought stress in the model legume Lotus japonicus was studied using a transcriptomic approach. Drought induced an extensive reprogramming of the transcriptome as related to various aspects of cellular metabolism, including genes involved in photosynthesis, amino acid metabolism and cell wall metabolism, among others. A particular focus was made on the genes involved in the cellular stress response. Key genes involved in the control of the cell cycle, antioxidant defense and stress signaling, were modulated as a consequence of water deprivation. Genes belonging to different families of transcription factors were also highly responsive to stress. Several of them were homologies to known stress-responsive genes from the model plant Arabidopsis thaliana, while some novel transcription factors were peculiar to the L. japonicus drought stress response. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Review

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Open AccessReview Adaptive and Pathogenic Responses to Stress by Stem Cells during Development
Cells 2012, 1(4), 1197-1224; doi:10.3390/cells1041197
Received: 2 September 2012 / Revised: 6 November 2012 / Accepted: 7 November 2012 / Published: 10 December 2012
Cited by 4 | PDF Full-text (1006 KB) | HTML Full-text | XML Full-text
Abstract
Cellular stress is the basis of a dose-dependent continuum of responses leading to adaptive health or pathogenesis. For all cells, stress leads to reduction in macromolecular synthesis by shared pathways and tissue and stress-specific homeostatic mechanisms. For stem cells during embryonic, fetal, [...] Read more.
Cellular stress is the basis of a dose-dependent continuum of responses leading to adaptive health or pathogenesis. For all cells, stress leads to reduction in macromolecular synthesis by shared pathways and tissue and stress-specific homeostatic mechanisms. For stem cells during embryonic, fetal, and placental development, higher exposures of stress lead to decreased anabolism, macromolecular synthesis and cell proliferation. Coupled with diminished stem cell proliferation is a stress-induced differentiation which generates minimal necessary function by producing more differentiated product/cell. This compensatory differentiation is accompanied by a second strategy to insure organismal survival as multipotent and pluripotent stem cells differentiate into the lineages in their repertoire. During stressed differentiation, the first lineage in the repertoire is increased and later lineages are suppressed, thus prioritized differentiation occurs. Compensatory and prioritized differentiation is regulated by at least two types of stress enzymes. AMP-activated protein kinase (AMPK) which mediates loss of nuclear potency factors and stress-activated protein kinase (SAPK) that does not. SAPK mediates an increase in the first essential lineage and decreases in later lineages in placental stem cells. The clinical significance of compensatory and prioritized differentiation is that stem cell pools are depleted and imbalanced differentiation leads to gestational diseases and long term postnatal pathologies. Full article
(This article belongs to the Special Issue Cellular Stress Response)
Open AccessReview Redox Mechanisms in Regulation of Adipocyte Differentiation: Beyond a General Stress Response
Cells 2012, 1(4), 976-993; doi:10.3390/cells1040976
Received: 28 September 2012 / Revised: 26 October 2012 / Accepted: 31 October 2012 / Published: 5 November 2012
Cited by 27 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text
Abstract
In this review, we summarize advances in our understanding of redox-sensitive mechanisms that regulate adipogenesis. Current evidence indicates that reactive oxygen species may act to promote both the initiation of adipocyte lineage commitment of precursor or stem cells, and the terminal differentiation [...] Read more.
In this review, we summarize advances in our understanding of redox-sensitive mechanisms that regulate adipogenesis. Current evidence indicates that reactive oxygen species may act to promote both the initiation of adipocyte lineage commitment of precursor or stem cells, and the terminal differentiation of preadipocytes to mature adipose cells. These can involve redox regulation of pathways mediated by receptor tyrosine kinases, peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), and CCAAT/enhancer binding protein β (C/EBPβ). However, the precise roles of ROS in adipogenesis in vivo remain controversial. More studies are needed to delineate the roles of reactive oxygen species and redox signaling mechanisms, which could be either positive or negative, in the pathogenesis of obesity and related metabolic disorders. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Open AccessReview Unfolded Protein Responses With or Without Unfolded Proteins?
Cells 2012, 1(4), 926-950; doi:10.3390/cells1040926
Received: 17 September 2012 / Revised: 15 October 2012 / Accepted: 22 October 2012 / Published: 1 November 2012
Cited by 3 | PDF Full-text (459 KB) | HTML Full-text | XML Full-text
Abstract
The endoplasmic reticulum (ER) is the site of secretory protein biogenesis. The ER quality control (QC) machinery, including chaperones, ensures the correct folding of secretory proteins. Mutant proteins and environmental stresses can overwhelm the available QC machinery. To prevent and resolve accumulation [...] Read more.
The endoplasmic reticulum (ER) is the site of secretory protein biogenesis. The ER quality control (QC) machinery, including chaperones, ensures the correct folding of secretory proteins. Mutant proteins and environmental stresses can overwhelm the available QC machinery. To prevent and resolve accumulation of misfolded secretory proteins in the ER, cells have evolved integral membrane sensors that orchestrate the Unfolded Protein Response (UPR). The sensors, Ire1p in yeast and IRE1, ATF6, and PERK in metazoans, bind the luminal ER chaperone BiP during homeostasis. As unfolded secretory proteins accumulate in the ER lumen, BiP releases, and the sensors activate. The mechanisms of activation and attenuation of the UPR sensors have exhibited unexpected complexity. A growing body of data supports a model in which Ire1p, and potentially IRE1, directly bind unfolded proteins as part of the activation process. However, evidence for an unfolded protein-independent mechanism has recently emerged, suggesting that UPR can be activated by multiple modes. Importantly, dysregulation of the UPR has been linked to human diseases including Type II diabetes, heart disease, and cancer. The existence of alternative regulatory pathways for UPR sensors raises the exciting possibility for the development of new classes of therapeutics for these medically important proteins. Full article
(This article belongs to the Special Issue Cellular Stress Response)
Open AccessReview Intricately Regulated: A Cellular Toolbox for Fine-Tuning XBP1 Expression and Activity
Cells 2012, 1(4), 738-753; doi:10.3390/cells1040738
Received: 10 August 2012 / Accepted: 25 September 2012 / Published: 15 October 2012
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Abstract
Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a signaling mechanism that allows cellular adaptation to ER stress by engaging pro-adaptive transcription factors and alleviating protein folding demand. One such transcription factor, X-box binding protein (XBP1), originates from the inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1) UPR stress sensor. XBP1 up-regulates a pool of genes involved in ER protein translocation, protein folding, vesicular trafficking and ER- associated protein degradation. Recent data suggest that the regulation of XBP1 expression and transcriptional activity may be a tissue- and stress-dependent phenomenon. Moreover, the intricacies involved in “fine-tuning” XBP1 activity in various settings are now coming to light. Here, we provide an overview of recent developments in understanding the regulatory mechanisms underlying XBP1 expression and activity and discuss the significance of these new insights. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Open AccessReview p53 -Dependent and -Independent Nucleolar Stress Responses
Cells 2012, 1(4), 774-798; doi:10.3390/cells1040774
Received: 12 September 2012 / Revised: 28 September 2012 / Accepted: 1 October 2012 / Published: 15 October 2012
Cited by 12 | PDF Full-text (332 KB) | HTML Full-text | XML Full-text
Abstract
The nucleolus has emerged as a cellular stress sensor and key regulator of p53-dependent and -independent stress responses. A variety of abnormal metabolic conditions, cytotoxic compounds, and physical insults induce alterations in nucleolar structure and function, a situation known as nucleolar or [...] Read more.
The nucleolus has emerged as a cellular stress sensor and key regulator of p53-dependent and -independent stress responses. A variety of abnormal metabolic conditions, cytotoxic compounds, and physical insults induce alterations in nucleolar structure and function, a situation known as nucleolar or ribosomal stress. Ribosomal proteins, including RPL11 and RPL5, become increasingly bound to the p53 regulatory protein MDM2 following nucleolar stress. Ribosomal protein binding to MDM2 blocks its E3 ligase function leading to stabilization and activation of p53. In this review we focus on a number of novel regulators of the RPL5/RPL11-MDM2-p53 complex including PICT1 (GLTSCR2), MYBBP1A, PML and NEDD8. p53-independent pathways mediating the nucleolar stress response are also emerging and in particular the negative control that RPL11 exerts on Myc oncoprotein is of importance, given the role of Myc as a master regulator of ribosome biogenesis. We also briefly discuss the potential of chemotherapeutic drugs that specifically target RNA polymerase I to induce nucleolar stress. Full article
(This article belongs to the Special Issue Cellular Stress Response)
Open AccessReview Multiple Strategies for Translesion Synthesis in Bacteria
Cells 2012, 1(4), 799-831; doi:10.3390/cells1040799
Received: 6 August 2012 / Revised: 29 September 2012 / Accepted: 30 September 2012 / Published: 15 October 2012
Cited by 4 | PDF Full-text (362 KB) | HTML Full-text | XML Full-text
Abstract
Damage to DNA is common and can arise from numerous environmental and endogenous sources. In response to ubiquitous DNA damage, Y-family DNA polymerases are induced by the SOS response and are capable of bypassing DNA lesions. In Escherichia coli, these Y-family [...] Read more.
Damage to DNA is common and can arise from numerous environmental and endogenous sources. In response to ubiquitous DNA damage, Y-family DNA polymerases are induced by the SOS response and are capable of bypassing DNA lesions. In Escherichia coli, these Y-family polymerases are DinB and UmuC, whose activities are modulated by their interaction with the polymerase manager protein UmuD. Many, but not all, bacteria utilize DinB and UmuC homologs. Recently, a C-family polymerase named ImuC, which is similar in primary structure to the replicative DNA polymerase DnaE, was found to be able to copy damaged DNA and either carry out or suppress mutagenesis. ImuC is often found with proteins ImuA and ImuB, the latter of which is similar to Y‑family polymerases, but seems to lack the catalytic residues necessary for polymerase activity. This imuAimuBimuC mutagenesis cassette represents a widespread alternative strategy for translesion synthesis and mutagenesis in bacteria. Bacterial Y‑family and ImuC DNA polymerases contribute to replication past DNA damage and the acquisition of antibiotic resistance. Full article
(This article belongs to the Special Issue Cellular Stress Response)
Open AccessReview The Inhibitor of Apoptosis (IAPs) in Adaptive Response to Cellular Stress
Cells 2012, 1(4), 711-737; doi:10.3390/cells1040711
Received: 31 July 2012 / Revised: 14 September 2012 / Accepted: 27 September 2012 / Published: 10 October 2012
Cited by 6 | PDF Full-text (1211 KB) | HTML Full-text | XML Full-text
Abstract
Cells are constantly exposed to endogenous and exogenous cellular injuries. They cope with stressful stimuli by adapting their metabolism and activating various “guardian molecules.” These pro-survival factors protect essential cell constituents, prevent cell death, and possibly repair cellular damages. The Inhibitor of [...] Read more.
Cells are constantly exposed to endogenous and exogenous cellular injuries. They cope with stressful stimuli by adapting their metabolism and activating various “guardian molecules.” These pro-survival factors protect essential cell constituents, prevent cell death, and possibly repair cellular damages. The Inhibitor of Apoptosis (IAPs) proteins display both anti-apoptotic and pro-survival properties and their expression can be induced by a variety of cellular stress such as hypoxia, endoplasmic reticular stress and DNA damage. Thus, IAPs can confer tolerance to cellular stress. This review presents the anti-apoptotic and survival functions of IAPs and their role in the adaptive response to cellular stress. The involvement of IAPs in human physiology and diseases in connection with a breakdown of cellular homeostasis will be discussed. Full article
(This article belongs to the Special Issue Cellular Stress Response)
Open AccessReview Virus-Heat Shock Protein Interaction and a Novel Axis for Innate Antiviral Immunity
Cells 2012, 1(3), 646-666; doi:10.3390/cells1030646
Received: 1 August 2012 / Revised: 24 August 2012 / Accepted: 27 August 2012 / Published: 11 September 2012
Cited by 6 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
Virus infections induce heat shock proteins that in turn enhance virus gene expression, a phenomenon that is particularly well characterized for the major inducible 70 kDa heat shock protein (hsp70). However, hsp70 is also readily induced by fever, a phylogenetically conserved response [...] Read more.
Virus infections induce heat shock proteins that in turn enhance virus gene expression, a phenomenon that is particularly well characterized for the major inducible 70 kDa heat shock protein (hsp70). However, hsp70 is also readily induced by fever, a phylogenetically conserved response to microbial infections, and when released from cells, hsp70 can stimulate innate immune responses through toll like receptors 2 and 4 (TLR2 and 4). This review examines how the virus-hsp70 relationship can lead to host protective innate antiviral immunity, and the importance of hsp70 dependent stimulation of virus gene expression in this host response. Beginning with the well-characterized measles virus-hsp70 relationship and the mouse model of neuronal infection in brain, we examine data indicating that the innate immune response is not driven by intracellular sensors of pathogen associated molecular patterns, but rather by extracellular ligands signaling through TLR2 and 4. Specifically, we address the relationship between virus gene expression, extracellular release of hsp70 (as a damage associated molecular pattern), and hsp70-mediated induction of antigen presentation and type 1 interferons in uninfected macrophages as a novel axis of antiviral immunity. New data are discussed that examines the more broad relevance of this protective mechanism using vesicular stomatitis virus, and a review of the literature is presented that supports the probable relevance to both RNA and DNA viruses and for infections both within and outside of the central nervous system. Full article
(This article belongs to the Special Issue Cellular Stress Response)
Open AccessReview Stress Response Pathways in Ameloblasts: Implications for Amelogenesis and Dental Fluorosis
Cells 2012, 1(3), 631-645; doi:10.3390/cells1030631
Received: 24 July 2012 / Revised: 2 August 2012 / Accepted: 20 August 2012 / Published: 30 August 2012
Cited by 7 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text
Abstract
Human enamel development of the permanent teeth takes place during childhood and stresses encountered during this period can have lasting effects on the appearance and structural integrity of the enamel. One of the most common examples of this is the development of [...] Read more.
Human enamel development of the permanent teeth takes place during childhood and stresses encountered during this period can have lasting effects on the appearance and structural integrity of the enamel. One of the most common examples of this is the development of dental fluorosis after childhood exposure to excess fluoride, an elemental agent used to increase enamel hardness and prevent dental caries. Currently the molecular mechanism responsible for dental fluorosis remains unknown; however, recent work suggests dental fluorosis may be the result of activated stress response pathways in ameloblasts during the development of permanent teeth. Using fluorosis as an example, the role of stress response pathways during enamel maturation is discussed. Full article
(This article belongs to the Special Issue Cellular Stress Response)

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