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Results for “replication stress”

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At least 271 records · Page 15Linked to original sources
PubMed1996

Impact of oxidative stress on human cytomegalovirus replication and on cytokine-mediated stimulation of endothelial cells.

Transplantation-related pathogenic factors such as ischemia or allograft-directed inflammation are associated with oxidative changes that might lead to cellular oxidative stress. The aim of this study was to investigate the impact of oxidative stress on: (1) CMV replication in cultured human endothelial cells and (2) the stimulation of endothelial cells by proinfiammatory cytokines. Both pathomechanisms are known to contribute to graft rejection crises in vivo. Oxidative stress was induced in endothelial cell cultures with 10-200 microM buthionine sulfoximine. Western blotting showed a significant increase in the production of CMV-specific immediate early and late proteins in buthionine sulfoximine-treated cultures. Immunocytochemical staining suggested that this effect was caused by increased numbers of CMV antigen expressing cells (66% immediate early; 78%, late). Quantitative polymerase chain reaction for CMV-specific DNA and virus titration revealed that enhanced viral replication levels correlated with increased virion production. As a measure for the endothelial cell activation status, the surface expression of HLA-ABC and HLA-DR and adhesion molecules (ICAM-1, ELAM-1, VCAM-1) was quantified by fluorometric methods. Whereas oxidative stress alone did not modulate any surface molecule expression, the IFN-gamma-mediated expression of HLA-ABC and HLA-DR and the IL-1-mediated expression of ICAM-1, but not of ELAM-1 and VCAM-1 (IL-1 + TNF-alpha), was amplified. Interestingly, the amplification of HLA molecule expression was even higher in CMV-infected endothelial cells. This study provides evidence that oxidative stress contributes to the regulation of CMV replication, virus shedding, and the activation of endothelial cells by proinflammatory cytokines as it is observed in transplant recipients.

Base Sequence↗
PubMed2026

Programmed ribosomal frameshifting triggers translational stress to promote viral replication.

Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.

RNA virus↗
PubMed2005

Adenovirus-mediated gene transfer in vivo: an approach to reduce oxidative stress.

Replication-deficient adenoviruses are used as vectors to study function of genes and to treat hypertension and cardiovascular diseases in preclinical studies. The purpose of this chapter is to provide an example of applications of the "first-generation," E1-deleted and partially E3-deleted, human adenovirus type 5 vector, to test the hypothesis that gene transfer of a primary antioxidant enzyme, human extracellular superoxide dismutase (ECSOD), reduces arterial pressure in a genetic animal model of hypertension. Two concepts in application of gene transfer in vascular biology are illustrated. First, the liver, by iv injection of an adenoviral vector, can function as the source for abundant amounts of a transgene product, with profound vascular effects, when the transgene encodes a secreted protein. Second, the specific function of a domain of the transgene product can be studied by preparation and injection of isogenic vectors that express the identical product with or without a domain.

Adenoviridae↗
PubMed1995

Relevance of oxidative stress to the limited replicative capacity of cultured human diploid cells: the limit of cumulative population doublings increases under low concentrations of oxygen and decreases in response to aminotriazole.

Human diploid cells, TIG-7, were serially cultivated under 1%, 5% or 21% (air) oxygen. The limit of their cumulative population doublings was extended by 16% or 10% under 1% or 5% oxygen, respectively, as compared with that under 21% oxygen. When TIG-7 cells were serially cultivated in the presence of 10 mM or 20 mM 3-amino-1H-1,2,4-triazole, an inhibitor of catalase scavenging hydrogen peroxide, the limit of their cumulative population doublings was shortened by 4.4% or 14.4%, respectively, as compared with untreated cells. In addition, long-term, rather than short-term, exposure of TIG-7 cells to aminotriazole retarded cell growth. Treatment with aminotriazole caused decreases not only in catalase activity but also in superoxide dismutase activity and reduced glutathione concentration, and an increase in glutathione peroxidase activity. These results suggest that the limit of the cumulative population doublings of human diploid cells is extended or shortened under decreasing or increasing oxidative stress, respectively. Oxidative stress may be relevant to replicative capacity, and a causative factor for oxidative stress may be hydrogen peroxide.

Amitrole↗
PubMed1985

Outcomes of role stress: a multisample constructive replication.

Responses from four separate samples of accountants and hospital employees provided a constructive replication of the Bedeian and Armenakis (1981) model of the causal nexus between role stress and selected outcome variables. We investigated the relationship between both role ambiguity and role conflict--as specific forms of role stress--and job-related tension, job satisfaction, and propensity to leave, using LISREL IV, a technique capable of providing statistical data for a hypothesized population model, as well as for specific causal paths. Results, which support the Bedeian and Armenakis model, are discussed in light of previous research.

Analysis of Variance↗
PubMed2005

Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays.

Human diploid fibroblasts (HDFs) exposed to subcytotoxic stress display many features of senescence. Using differential display RT-PCR, gene expression of HDFs in premature senescence induced by tert-butylhydroperoxide or ethanol and in replicative senescence was compared to gene expression of HDFs at early cumulative population doublings. Thirty genes of known function were identified from the 265 differentially displayed cDNA fragments. A customized low-density array allowed to confirm the relative level of the corresponding 30 transcripts. We found differential expression of genes coding for proteins implicated namely in growth arrest (PTEN, IGFBP-3, LRP-1 and CAV1), senescent morphogenesis (TGF-beta1 and LOXL2) and iron metabolism (TFR and FTL).

Cellular Senescence↗
PubMedDate not supplied

Caregiving and developmental factors differentiating young at-risk urban children showing resilient versus stress-affected outcomes: a replication and extension.

This study tested hypotheses from an organizational-developmental model for childhood resilience. In this model resilience reflects a child's mastery of age-salient objectives, in the face of substantial adversity, by drawing on internal and external resources that enhance processes of adaptation specific to each developmental stage. Interviews were conducted with parents of 122 7- to 9-year-old urban children exposed to multiple risk factors, 69 classified as resilient and 53 as maladjusted. Consistent with predictions generated by the model: (1) characteristics of a child's caregiving system and early development differentiated children with resilient and stress-affected adaptations; and (2) variables reflecting emotionally responsive, competent parenting were direct, proximal predictors of resilient status and mediators of other caregiver resources such as education, mental health, and relational history. Identified predictors of resilient status, including competent parenting and caregiver psychosocial resources, largely replicated findings from a prior study with sociodemographically comparable 9- to 12-year-old children.

Adaptation, Psychological↗
PubMed2005

A bacterial G protein-mediated response to replication arrest.

To define factors in E. coli promoting survival to replication fork stress, we isolated insertion mutants sensitive to replication inhibitors. One insertion caused partial loss of the universally conserved GTPase, obgE/yhbZ gene. Although obgE is essential for growth, our insertion allele supported viability until challenged with various replication inhibitors. A mutation designed to negate the GTPase activity of the protein produced similar phenotypes, but was genetically dominant. Synergistic genetic interactions with recA and recB suggested that chromosome breaks and regressed forks accumulate in obgE mutants. Mutants in obgE also exhibited asynchronous overreplication during normal growth, as revealed by flow cytometry. ObgE overexpression caused SeqA foci, normally localized to replication forks, to spread extensively within the cell. We propose that ObgE defines a pathway analogous to the replication checkpoint response of eukaryotes and acts in a complementary way to the RecA-dependent SOS response to promote bacterial cell survival to replication fork arrest.

Adenosine Triphosphatases↗
PubMed2000

Autonomic and neuroendocrine responses to mild psychological stressors: effects of chronic stress on older women.

We investigated autonomic and endocrine responses to acute stressors in 27 women who were or are presently caring for a spouse with a progressive dementia (high chronic stress) and 37 noncaregivers who were category matched for age and family income (low chronic stress). Measures were taken before (low acute stress) and in response to brief laboratory stressors (high acute stress). We replicated prior research showing that caregivers report greater stress, depression, and loneliness than the comparison groups, and acute stressors elevate autonomic and neuroendocrine activity. We also found that caregivers, relative to noncaregivers, exhibited shorter preejection periods and elevated blood pressure and heart rate, but the magnitude of autonomic and neuroendocrine reactivity to the experimental stressors was comparable across these groups. This pattern of autonomic differentiation replicates prior research showing that caregivers are characterized by higher sympathetic activation than noncaregivers and suggests that the effects of chronic stress on physiological reactivity may be a less robust effect in older adults.

Adaptation, Psychological↗
PubMed1987

An investigation of emphatic stress comprehension in adult aphasia: a replication.

The differential effects of normal and emphatic stress on the auditory comprehension performance of 9 aphasic and 5 normal adults were assessed. As a partial replication of Pashek and Brookshire (1982), four paragraph-length stimuli were used from the original study. Each paragraph was presented twice. One version was recorded with one fact per sentence receiving normal stress, the second version with emphatic stress. Following each paragraph, subjects answered 16 "yes/no" questions about the eight target facts in each paragraph. This procedure allowed for direct comparison of performance across conditions on the same paragraph rather than on different paragraphs as in the original study. Analysis of the results revealed that the aphasic subjects demonstrated significantly better performance for stimuli presented with emphatic stress. In addition, no significant learning effect was observed over two repetitions of each paragraph. These data are interpreted as successfully replicating the findings of Pashek and Brookshire. The results suggest that emphatic stress plays an important role in auditory comprehension. However, the observed effect of emphatic stress should not be attributed solely to changes incumbent upon the stress bearing word. Alternative explanations are discussed.

Aged↗
PubMed1988

Simple laboratory experiments to replicate some of the stresses on vertebro-basilar arterial walls. An investigation of possible mechanisms of traumatic subarachnoid haemorrhage.

The hypothesis that reversed blood flow in transiently occluded vertebral arteries may be responsible for some cases of massive traumatic subarachnoid haemorrhage has been investigated in vitro. Simple laboratory tests were performed on 25 vertebro-basilar arterial systems, and succeeded in producing either longitudinal tears in normally structured vertebral arteries, or tears at the origin of the posterior inferior cerebellar arteries. The results indicated that under such conditions, with systolic blood pressure in the physiological range, reversed blood flow had different characteristics and stressed the arterial wall to the point where it yielded.

Adult↗
PubMed2001

p53 Protects renal inner medullary cells from hypertonic stress by restricting DNA replication.

We previously found that p53 upregulation by hypertonicity protected renal inner medullary collecting duct (mIMCD3) cells from apoptosis. The purpose of the present study was to investigate the mechanism by which p53 protects the cells. We now find that hypertonicity (NaCl added to a total of 500 mosmol) inhibits DNA replication and delays G(1)-S transition as concluded from analysis of cell cycle distributions and bromodeoxyuridine (BrDU) incorporation rates. Lowering of p53 with p53 antisense oligonucleotide attenuated such effects of hypertonicity, resulting in an increased number of apoptotic cells in S phase and cells with >4 N DNA. Results with synchronized cells are similar, showing that cells in the early S phase are more sensitive to hypertonicity. Immunocytochemistry revealed that p53 becomes phosphorylated on Ser(15) and translocates to the nucleus in S both in isotonic and hypertonic conditions. Caffeine (2 mM) greatly reduces the p53 level and Ser(15) phosphorylation, followed by a remarkable increase of DNA replication rate, by failure of hypertonicity to inhibit it, and by reduction of cell number during hypertonicity. Finally, inhibition of DNA replication by the DNA polymerase inhibitor aphidicolin significantly improves cell survival, confirming that keeping cells in G(1) and decreasing the rate of DNA replication is protective and that these actions of p53 most likely are what normally help protect cells against hypertonicity.

Animals↗
PubMed1986

The stresses of psychotherapeutic work: a replication and extension.

The present study represents a replication and extension of a recent investigation of the patterns of stresses in psychotherapeutic work. A sample of 227 licensed psychologists who were practicing in Northern California were administered two Likert-type rating scales, which were expanded versions of questionnaires originally developed by Farber and Heifitz (1981). Factor analysis of the data revealed that the stressful aspects of therapeutic work include maintaining the therapeutic relationship, scheduling difficulties, professional doubt, work overinvolvement, and feeling personally depleted. In addition, stressful patient behaviors were found to cluster into five distinct categories: Expressions of negative affect, resistances, psychopathological symptoms, suicidal threats, and passive-aggressive behaviors. Demonstration of the empirical generalizability of the factor structure and of the relative importance of stressful therapeutic events argues for the usefulness of the extended versions of The Therapeutic Stresses and Stressful Patient Behaviors rating scales.

Adult↗
PubMed2004

Loss of proliferative capacity and induction of senescence in oxidatively stressed human fibroblasts.

Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute to aging. To investigate the role of cellular senescence in aging it is necessary to define the time-dependent molecular events by which it is characterized. Here we investigated changes in levels of key proteins involved in cell cycle regulation, DNA replication, and stress resistance in senescing human fibroblasts following oxidative stress. An immediate response in stressed cells was dephosphorylation of retinoblastoma (Rb) and cessation of DNA synthesis. This was followed by sequential induction of p53, p21, and p16. Increase in hypophosphorylated Rb and induction of p53 and p21 by a single stress treatment was transient, whereas sustained induction or dephosphorylation were achieved by a second stress. Down-regulation of the critical DNA replication initiation factor Cdc6 occurred early after stress concurring with p53 induction, and was followed by a decrease in Mcm2 levels. A late event in the stress-induced molecular sequence was the induction of SOD1, catalase, and HSP27 coinciding with development of the fully senescent phenotype. Our data suggest that loss of proliferative capacity in oxidatively stressed cells is a multistep process regulated by time-dependent molecular events that may play differential roles in induction and maintenance of cellular senescence.

Blotting, Western↗
PubMed2000

Role of oxidative stress in telomere length regulation and replicative senescence.

Replicative senescence is tied into organismal aging processes in more than one respect, and telomeres appear to be the major trigger of replicative senescence under many conditions in vitro and in vivo. However, the structure-function relationships in telomeres, the mechanisms of telomere shortening with advancing replicative age, and the regulation of senescence by telomeres are far from understood. Combining recent data on telomere structure, function of telomere-binding proteins, and sensitivity of telomeres to oxidative damage, an integrative model of telomere shortening and signaling is developed. The model suggests that t-loop formation hinders access of repair proteins to telomeres, leading to accumulation of a basic sites and single-strand breaks. These might contribute to accelerated telomere shortening by transient stalling of replication as well as, if present in high concentrations, to a relief of torsional tension which might destabilize the telomeric loop structure. As a result, the single-stranded G-rich overhang, which is present at the very ends of telomeres but is normally protected at the base of the telomeric loop, will be exposed to the nucleoplasm. Free G-rich telomeric single strands are a strong inductor of the p53 pathway, and exposure of the overhangs seems to be the first step in the signal transduction cascade to replicative senescence.

Animals↗
PubMed2005

Novel checkpoint response to genotoxic stress mediated by nucleolin-replication protein a complex formation.

Human replication protein A (RPA), the primary single-stranded DNA-binding protein, was previously found to be inhibited after heat shock by complex formation with nucleolin. Here we show that nucleolin-RPA complex formation is stimulated after genotoxic stresses such as treatment with camptothecin or exposure to ionizing radiation. Complex formation in vitro and in vivo requires a 63-residue glycine-arginine-rich (GAR) domain located at the extreme C terminus of nucleolin, with this domain sufficient to inhibit DNA replication in vitro. Fluorescence resonance energy transfer studies demonstrate that the nucleolin-RPA interaction after stress occurs both in the nucleoplasm and in the nucleolus. Expression of the GAR domain or a nucleolin mutant (TM) with a constitutive interaction with RPA is sufficient to inhibit entry into S phase. Increasing cellular RPA levels by overexpression of the RPA2 subunit minimizes the inhibitory effects of nucleolin GAR or TM expression on chromosomal DNA replication. The arrest is independent of p53 activation by ATM or ATR and does not involve heightened expression of p21. Our data reveal a novel cellular mechanism that represses genomic replication in response to genotoxic stress by inhibition of an essential DNA replication factor.

Ataxia Telangiectasia Mutated Proteins↗