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PubMed1992

A possible factor in genetic instability of cancer cells: stress-induced secreted proteins lead to decrease in replication fidelity.

Ultraviolet irradiation triggers a response in mammalian cells known as the UV response. Part of the UV response forms the enhanced synthesis of various extracellular proteins able to transmit the response to non-irradiated cells. Because several cancer-prone syndromes with enhanced genetic instability also have an enhanced synthesis of the same set of proteins without prior stimulation it is possible that induction of these stress responsive proteins may be involved in the process of carcinogenesis and genetic instability. To test this hypothesis mouse T lymphoma cells, GRSL13, were treated with the conditioned medium of UV-induced cells under various experimental conditions. Overall the mutation rate is enhanced 1.8-fold (P < 0.01). However, the degree of enhancement is strongly influenced by culture conditions. UV-induced factors only lead to an enhanced mutation rate when cells, both for the production and response to those factors, originate from a similar cell density. In addition, it was found that fresh medium interferes with this response. To eliminate the hindrance of these factors on the effect of the conditioned medium on the mutation rate, serum-starved cells at high density were treated with serum-free medium derived from high-density UV-irradiated cultures. Using these conditions a 2.8-fold (P < 0.002) enhancement of the mutation rate was found. Fluctuation analysis indicated that the enhancement is 10-fold during the first five generations after treatment. UV-induced factors have also been found to induce cell growth, and the degree of induction was linearly correlated with the enhancement in mutation rate. These experiments are in agreement with the hypothesis that induction of stress responses leads to genetic instability.

Animals↗
PubMed2026

Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.

Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.

Integrated stress response (ISR)↗
PubMed1990

Replication of Langat virus in immunocompetent cells of mice subjected to immobilization stress.

Immobilization stress (hypokinesis) in Balb/c mice may aggravate asymptomatic infection with Langat virus (strain TP-21) as evidenced by 4-fold increased lethality in comparison with control animals. The virus levels in the spleen and brain of stressed and infected mice and the in vitro yield of the virus in immunocompetent cells derived from stressed mice were significantly higher than in controls. Enhanced virus replication in latter cells may contribute to increased accumulation of the infectious agent in lymphatic tissues, which would facilitate virus invasion into CNS followed with acute disease and death of animals.

Animals↗
PubMed2002

Stress-induced premature senescence: from biomarkers to likeliness of in vivo occurrence.

The similarities between the biomarkers of stress-induced premature senescence and replicative senescence are reviewed. The possibility of existence of 'molecular scars', i.e. long-term changes observed after subcytotoxic stress and not observed in replicative senescence, is considered. Lastly, the likeliness of existence of stress-induced premature senescence in vivo is discussed. The possible effects on normal and pathological tissue ageing are predicted.

Aging, Premature↗
PubMed2005

The p53 pathway: positive and negative feedback loops.

The p53 pathway responds to stresses that can disrupt the fidelity of DNA replication and cell division. A stress signal is transmitted to the p53 protein by post-translational modifications. This results in the activation of the p53 protein as a transcription factor that initiates a program of cell cycle arrest, cellular senescence or apoptosis. The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response. There are at least seven negative and three positive feedback loops described here, and of these, six act through the MDM-2 protein to regulate p53 activity. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene products. There are at least three different ubiquitin ligases that can regulate p53 in an autoregulatory manner: MDM-2, Cop-1 and Pirh-2. The meaning of this redundancy and the relative activity of each of these feedback loops in different cell types or stages of development remains to be elucidated. The interconnections between signal transduction pathways will play a central role in our understanding of cancer.

Amino Acid Sequence↗
PubMed2000

Stress, alcohol use and alcohol-related problems: the influence of negative and positive affect in two cohorts of young adults.

OBJECTIVE: Past research has suggested that trait-based positive and negative affect mediate the relationships between self-report measures of stress and health. We extended these assumptions to the study of health-related behaviors, specifically the much studied stress-alcohol relationship. In addition, we sought to replicate previous findings showing that stress is more strongly associated with alcohol problems and not alcohol use as many theories (e.g., tension-reduction hypothesis) have assumed. METHOD: Structural equation modeling was used to test a mediating variable model in two cohorts (574 and 239 subjects) of randomly selected young adults between 18 and 35 years of age. Participants were from the 1996 data wave of the Niagara Young Adult Health Study, a community-based study incorporating a modified cohort-sequential design. The larger (older) cohort consisted of subjects initially contacted in 1990. RESULTS: For both cohorts, the measurement model proved to be very reliable. The final structural models did not match the predicted model. The correlations between the Stress and Alcohol Use latent variables (necessary to test a mediational model) were not significant in either cohort. However, in the older cohort, trait-based positive affect and hostility acted as intervening variables, allowing for an indirect relationship between stress and alcohol use. In the younger cohort, this indirect pattern was not present because none of the latent affect variables led to alcohol use. In both cohorts, stress predicted alcohol problems, even after controlling for the relationships between stress, affect and alcohol use. Significant cohort differences in the structural models were observed. CONCLUSIONS: The assumptions regarding the mediation of affect on the relationship between stress and health cannot be extended completely to the stress-alcohol relationship. Two reasons for this are: (1) the differences between the two age cohorts in the relationships between stress, affect and alcohol use and (2) the finding that stress is more predictive of alcohol-related problems than it is of alcohol use.

Adult↗
PubMed2005

Molecular events in kidney ageing.

PURPOSE OF REVIEW: Ageing of the kidney is a problem of clinical and basic interest. The problem of renal dysfunction and end-stage renal disease is a major burden on the health system, and old donor age is a major limitation on the use of donor organs and on survival of transplanted kidneys. Moreover, stresses linked to nephropathies, postoperative stress, inflammation and allograft rejection can lead to premature senescence of renal cells thus accelerating organ atrophy. Age-related and disease or stress-related nephron loss could reflect both the limited ability of epithelial cells to repair and replicate in the face of environmental stresses, and limitations on the number of cell replications caused by telomere shortening. Therefore, elucidating cellular senescence mechanisms is relevant to kidney diseases and kidney transplantation. RECENT FINDINGS: Recent findings suggest additive effects of replicative and environmental stress-induced senescence in cellular and organ ageing. In particular, ATM/p53/p21 and Ras/p38/p16 pathways have been shown to co-contribute to the overall cellular senescence, which is caused by extrinsic and intrinsic stimuli. Moreover, the role of epigenetic factors, including protein acylation/deacetylation, chromatin remodeling or caloric restriction, is the focus of recent studies on ageing and senescence. SUMMARY: Despite significant progress, cellular senescence is still better understood in vitro than in vivo. So far, p16 remains the best marker of chronological age in the kidney, and can be considered as an indicator of premature senescence caused by stresses or disease. The beneficial effects of caloric restriction on organ ageing and the role of histone acetylation in pathologic states in rodents are of considerable interest, and deserve future studies.

Aging↗
PubMed1997

Auditory event-related potentials to tone stimuli in combat-related posttraumatic stress disorder.

This study attempted to replicate findings of abnormal auditory event-related potentials (ERPs) in posttraumatic stress disorder (PTSD) in a sample of Vietnam combat veterans. Veterans with combat-related PTSD, divided into unmedicated (unmed-PTSD, n = 12) and medicated (med-PTSD, n = 22) groups, and veterans without PTSD (non-PTSD, n = 10) completed a three-tone "oddball" target detection task while ERPs were measured. Individuals with comorbid panic disorder (PD) were excluded from the primary analyses. Parietal P3 amplitude to the target tone was significantly smaller in unmed-PTSD compared to med-PTSD and non-PTSD groups. These differences did not remain significant when an adjustment was made for level of depression. Parietal P3 amplitude was also negatively correlated with state anxiety. Secondary analyses within the unmed-PTSD group indicated that participants with comorbid PD (n = 3) had the largest parietal P3 amplitudes to target tones. Results are consistent with attentional or concentration deficits in PTSD and highlight the importance of considering comorbid diagnoses. The absence of ERP differences between med-PTSD and non-PTSD participants suggests that psychotropic medication may normalize these deficits.

Acoustic Stimulation↗
PubMed2002

Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis.

Cells subjected to sub-lethal doses of stress such as irradiation or oxidative damage enter a state that closely resembles replicative senescence. What triggers stress-induced premature senescence (SIPS) and how similar this mechanism is to replicative senescence are not well understood. It has been suggested that stress-induced senescence is caused by rapid telomere shortening resulting from DNA damage. In order to test this hypothesis directly, we examined whether overexpression of the catalytic subunit of human telomerase (hTERT) can protect cells from SIPS. We therefore analyzed the response of four different lines of normal human fibroblasts with and without hTERT to stress induced by UV, gamma-irradiation, and H(2)O(2). SIPS was induced with the same efficiency in normal and hTERT-immortalized cells. This suggests that SIPS is not triggered by telomere shortening and that nonspecific DNA damage serves as a signal for induction of SIPS. Although telomerase did not protect cells from SIPS, fibroblasts expressing hTERT were more resistant to stress-induced apoptosis and necrosis. We hypothesize that healing of DNA breaks by telomerase inhibits the induction of cell death, but because healing does not provide legitimate DNA repair, it does not protect cells from SIPS.

Apoptosis↗
PubMedDate not supplied

[The effect of emotional-pain stress on the rate of DNA synthesis in heart and liver cells].

Effect of a single long-term (6 hrs) emotional-painful stress on DNA synthesis was studied in nuclei and mitochondria of heart and liver cells. Various systems of DNA synthesis in heart and liver cells were shown to respond dissimilarly to the stress. The rates of replication and reparative synthesis of nuclear DNA were increased while synthesis of mitochondrial DNA was unaltered in heart cells within the first day after the stress. In liver cells the reparative synthesis of nuclear DNA was also increased, whereas the rate of its replication in nuclei and mitochondria was distinctly inhibited for a long time. Thus, the systems of DNA synthesis in liver cells proved to be more sensitive to extreme stress-reactions as compared with heart cells. Effect of the stress on the systems of DNA synthesis in specific and connective tissue cells of liver and heart is discussed. At the same time, mitochondria are localized in specialized cells of both heart and liver tissues. The data obtained suggest that inhibition of the mitochondrial DNA synthesis is realized in hepatocytes.

Animals↗
PubMed2001

ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1.

Chk1 is an evolutionarily conserved protein kinase that regulates cell cycle progression in response to checkpoint activation. In this study, we demonstrated that agents that block DNA replication or cause certain forms of DNA damage induce the phosphorylation of human Chk1. The phosphorylated form of Chk1 possessed higher intrinsic protein kinase activity and eluted more quickly on gel filtration columns. Serines 317 and 345 were identified as sites of phosphorylation in vivo, and ATR (the ATM- and Rad3-related protein kinase) phosphorylated both of these sites in vitro. Furthermore, phosphorylation of Chk1 on serines 317 and 345 in vivo was ATR dependent. Mutants of Chk1 containing alanine in place of serines 317 and 345 were poorly activated in response to replication blocks or genotoxic stress in vivo, were poorly phosphorylated by ATR in vitro, and were not found in faster-eluting fractions by gel filtration. These findings demonstrate that the activation of Chk1 in response to replication blocks and certain forms of genotoxic stress involves phosphorylation of serines 317 and 345. In addition, this study implicates ATR as a direct upstream activator of Chk1 in human cells.

Adenoviridae↗
PubMed2006

Cellular stress rather than stage of the cell cycle enhances the replication and plating efficiencies of herpes simplex virus type 1 ICP0- viruses.

This lab reported previously that the plating efficiency of a herpes simplex virus type 1 ICP0-null mutant was enhanced upon release from an isoleucine block which synchronizes cells to G1 phase (W. Cai and P. A. Schaffer, J. Virol. 65:4078-4090, 1991). Peak plating efficiency occurred as cells cycled out of G1 and into S phase, suggesting that the enhanced plating efficiency was due to cellular activities present in late G1/early S phase. We have found, however, that the enhanced plating efficiency did not occur when cells were synchronized by alternative methods. We now report that the plating efficiency of ICP0- viruses is not enhanced at a particular stage of the cell cycle but rather is enhanced by specific cellular stresses. Both the plating and replication efficiencies of ICP0- viruses were enhanced as much as 25-fold to levels similar to that of wild-type virus when monolayers were heat shocked prior to infection. In addition to heat shock, UV-C irradiation but not cold shock of monolayers prior to infection resulted in enhanced plating efficiency. We further report that the effect of cellular stress is transient and that cell density rather than age of the monolayers is the primary determinant of ICP0- virus plating efficiency. As both cell stress and ICP0 are required for efficient reactivation from latency, the identification of cellular activities that complement ICP0- viruses may lead to the identification of cellular activities that are important for reactivation from neuronal latency.

Animals↗
PubMed1997

Assessing homosexual stress.

The present study was designed to replicate and extend an existing technique for assessing homosexual stress using Personal Construct Theory. In addition to using difference scores between present and homosexual self-ratings on subjects' personal construct rating dimensions to determine homosexual stress, difference scores between ideal and homosexual selves were also studied to determine if this method would represent a more accurate assessment of homosexual stress. Levels of homosexual stress were obtained for each subject from each technique and were correlated with attitudes toward homosexuality. The influence of construct meaningfulness and level of homosexual stress on attitudes toward homosexuality was also explored to determine if higher stress on more meaningful constructs yields more negative attitudes. The results of this study revealed that each stress technique was significantly and equivalently positively correlated with negative attitudes toward homosexuality. Homosexual stress was found to be independent of the meaningfulness measures used but positively correlated with authoritarianism.

Analysis of Variance↗
PubMed2006

AIB1 promotes DNA replication by JNK repression and AKT activation during cellular stress.

Amplified in breast cancer 1 (AIB1) is a member of the p160 family of nuclear receptor coactivator protein. Recent studies have reported that high-level AIB1 production is involved in the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway for progression to malignant carcinoma in a steroid-independent manner. Here we demonstrate that, in AIB1-knockout DT40 chicken B-lymphocytes, loss of AIB1 results in induction of phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, in addition to the inhibition of DNA replication. In contrast, high-level AIB1 production prevents proapoptotic activation of the JNK/c-Jun signal transduction pathway and induces DNA replication through phosphorylation of the Akt/p65 NF-kappaB subunit RelA under cellular stresses such as UV irradiation or serum deprivation. Moreover, we have found that AIB1 is essential for the phosphorylation of histone H3 at serine 10, which is associated with the signal transduction to chromatin, leading to the transient expression of immediate-early genes in response to UV stimulation. Our results therefore suggest that AIB1 directly links to cell cycle control mechanisms in concern with the balance between apoptosis and proliferation.

Animals↗
PubMed2005

High plasticity of the hepatitis B virus capsid revealed by conformational stress.

Hepatitis B virus (HBV) replicates through reverse transcription inside its icosahedral nucleocapsid. The internal genome status is signaled to the capsid surface, predicting regulated conformational changes in the capsid structure. To probe their nature and extent, we imposed local conformational stress on the outer surface of HBV capsid-like particles, and monitored its consequences by electron cryomicroscopy and image reconstruction. The capsid structure had an enormous flexibility and robustness as a whole, as well as within the subunits, whose spikes were able to rotate by as much as 40 degrees against the distal interdimer contact sites. The likely hinge for the swiveling movement was the conserved Gly111 residue at the inner surface of the capsid. The stress imposed from the outside also affected the internal capsid organization, implying a specific route for the flow of conformational information between capsid interior and exterior as required for signaling of the genome status.

Amino Acid Sequence↗
PubMed1997

In vitro fatigue of human tendons.

The purpose of this study was to determine the fatigue behaviour of human tendons in vitro. The testing was accomplished with the use of specially designed grips and the local measurement of tendon cross-sectional area. Ninety specimens prepared from Extensor digitorum longus (EDL) tendons of the foot were subjected to a cyclic square tension-tension stress waveform at physiological frequencies. The maximum tensile stress was normalised to values corresponding to prescribed levels between 10% and 90% of the calculated ultimate tensile strength (UTS) of 100 MPa. The minimum stress was set at 1% of the UTS. A replication of 10 specimens per stress level allowed the use of statistical models for the distribution of fatigue life. Results followed a linear model, of form S = 101.3 - 14.8 log(N), relating the normalised stress to the median number of cycles to failure, therefore suggesting the absence of an endurance limit. The Weibull distribution was found to describe adequately the probability of failure at each stress level. A model which takes into account in vivo healing was proposed. This model was able to explain the presence of intact tendons throughout the lifetime of an individual.

Aged↗
PubMed1997

Stress, alcohol-related expectancies and coping preferences: a replication with adolescents of the Cooper et al. (1992) model.

OBJECTIVE: The present study attempted to replicate with adolescents the stressor vulnerability model of adult drinking proposed by Cooper et al. (J. Abnorm. Psychol. 101: 139-152, 1992). The Cooper et al. model simultaneously assesses the stress-moderating effects of gender, expectancies and coping on alcohol use and abuse. METHOD: Adolescents in Grades 7-12 (N = 184, 59% female) completed the Alcohol Expectancy Questionnaire-Adolescent form, the COPE, the Adolescent Perceived Events Scale and the Drinking to Cope scale. RESULTS: The pattern of results was very similar to those of earlier studies using adults or undergraduates. Generally, positive expectancies for alcohol, an avoidant coping preference and stress were predictive of drinking to cope, alcohol use and alcohol-related problems. A number of two-way interactions were also reported. Although gender did not play a prominent role in prediction, as it typically does with adults, grade was a significant predictor; older students reported more alcohol use and alcohol-related problems than younger students. CONCLUSIONS: Results were similar to those reported by Cooper et al. with adults and Evans and Dunn (J. Stud. Alcohol 56: 186-193, 1995) with undergraduates, and support the utility of the stressor vulnerability model for understanding alcohol use among adolescents.

Adaptation, Psychological↗