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Results for “Replication stress response”

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PubMed1995

Enhanced human T-cell lymphotropic virus type I expression following induction of the cellular stress response.

Human T-cell lymphotropic virus type I (HTLV-I) infection is typically associated with long incubation periods between virus exposure and disease manifestation. Although viral protein expression is considered to play an important role in the pathogenesis of HTLV-I-associated diseases, limited information is known regarding host cell mechanisms that control viral gene expression. This study was designed to evaluate modulation of HTLV-I gene expression following induction of the cellular stress response in HTLV-I-infected lymphocytes. The cellular stress response was elicited by treatment with either Na arsenite or thermal stress and was monitored by demonstrating increased expression of the 72-kDa heat shock protein. Induction of the cellular stress response in HTLV-I-infected lymphocytes resulted in significantly increased HTLV-I-mediated syncytia formation due to enhanced HTLV-I envelope (gp46) expression. Intracellular viral proteins and released p24 capsid protein were increased in stressed infected lymphocytes as compared to nonstressed infected lymphocytes. Furthermore, HTLV-I-LTR reporter gene constructs had increased activity (three- to sixfold) in a transiently transfected, uninfected lymphocyte cell line following induction of the cellular stress response. Quantitation of HTLV-I RNA expression by slot blot analysis of infected lymphocytes suggested variable increases in RNA accumulation. Northern blot analysis demonstrated no qualitative changes in expression of RNA species. These data suggest a relationship between modulation of viral replication and a basic cellular response to stress and have important implications for understanding host cell control mechanisms of HTLV-I expression.

Arsenites↗

PubMed2005

Activation of endoplasmic reticulum stress response by hepatitis C virus proteins.

Flaviviruses utilize the endoplasmic reticulum (ER) as the main site for replication and protein synthesis and cause some level of ER stress. In the present study, we evaluated the ability of HCV proteins to induce ER stress response by using a tetracycline-regulated cell line expressing a region of HCV genome containing the structural genes. In this system different levels of HCV protein expression could be obtained by varying the concentration of tetracycline in the medium. Real Time PCR and Western blotting assay demonstrated that HCV mRNA and protein levels reach a maximum value at 24-48 h and decrease at 72 h postinduction. Cell proliferation analysis indicated that HCV synthesis causes cell growth inhibition. The effect was also observed in cells expressing lower levels of HCV proteins. The expression profile of specific genes, which are markers of ER stress response, revealed the upregulation of the chaperone GRP78 and the transcription factor GADD153. Induction of GADD153 correlates with the downregulation of the antiapoptotic Bcl-2 gene suggesting that synthesis of HCV proteins may influence cell fate through the activation of ER stress signaling pathway.

CCAAT-Enhancer-Binding Proteins↗

PubMed2006

A DNA integrity network in the yeast Saccharomyces cerevisiae.

A network governing DNA integrity was identified in yeast by a global genetic analysis of synthetic fitness or lethality defect (SFL) interactions. Within this network, 16 functional modules or minipathways were defined based on patterns of global SFL interactions. Modules or genes involved in DNA replication, DNA-replication checkpoint (DRC) signaling, and oxidative stress response were identified as the major guardians against lethal spontaneous DNA damage, efficient repair of which requires the functions of the DNA-damage checkpoint signaling and multiple DNA-repair pathways. This genome-wide genetic interaction network also identified novel components (DIA2, NPT1, HST3, HST4, and the CSM1 module) that potentially contribute to mitotic DNA replication and genomic stability and revealed novel functions of well-studied genes (the CTF18 module) in DRC signaling. This network will guide more detailed characterization of mechanisms governing DNA integrity in yeast and other organisms.

Chromosomal Proteins, Non-Histone↗

PubMed2005

Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor.

The constitutive androstane receptor (CAR, NR1I3) is a central regulator of xenobiotic metabolism. CAR activation induces hepatic expression of detoxification enzymes and transporters and increases liver size. Here we show that CAR-mediated hepatomegaly is a transient, adaptive response to acute xenobiotic stress. In contrast, chronic CAR activation results in hepatocarcinogenesis. In both acute and chronic xenobiotic responses, hepatocyte DNA replication is increased and apoptosis is decreased. These effects are absent in CAR null mice, which are completely resistant to tumorigenic effects of chronic xenobiotic stress. In the acute response, direct up-regulation of Mdm2 expression by CAR contributes to both increased DNA replication and inhibition of p53-mediated apoptosis. These results demonstrate an essential role for CAR in regulating both liver homeostasis and tumorigenesis in response to xenobiotic stresses, and they also identify a specific molecular mechanism linking chronic environmental stress and tumor formation.

Animals↗

PubMed2006

Reactivation from quiescence does not coincide with a global induction of herpes simplex virus type 1 transactivators.

Herpes simplex virus type 1 (HSV-1) reactivates from a small fraction of latently infected neurons in vivo and neuronally differentiated (ND), quiescently infected (QIF)-PC12 cells in vitro. This may be the result of reactivation initiating in only a few cells, or reactivation followed by premature termination of the productive virus life cycle in many or even a majority of cells. To examine the viral stress response, HSV-1 promoters of representative alpha, beta, and gamma class genes were examined in ND- and QIF-PC12 cells after treatments with agents known to induce reactivation. HSV-1 promoters displayed variable levels of basal gene expression in ND-PC12 cells ranging from 2 to 1,200 times the level of the control vector pGL3-Basic. Expression of the latency associated transcript (LAT) was greatest, with representatives of the alpha class exhibiting greater expression than the beta and gamma classes. The HSV-1 promoters examined did not respond dramatically to stress treatments. The viral gene response was also measured during the initiation of reactivation of a cryptic HSV-1 genome after forskolin treatment, under conditions that restricted DNA replication. During the first 24 h after stress induction the response was limited. By 48 h post-forskolin treatment, only modest increases occurred for ICP0, ICP4, and LAT transcripts, reaching levels of no greater than 2.2 times mock treated levels. In contrast, ICP27, ribonucleotide reductase (RR), and VP16 promoters did not respond. These findings indicate that reactivation from QIF-PC12 cells does not result in a global response of the specific HSV-1 genes tested, when assessed at the population level. These data support the hypothesis that stress-induced reactivation initiates in a minority of cells.

Animals↗

PubMed2006

DNA methyltransferase 1 knockdown activates a replication stress checkpoint.

DNA methyltransferase 1 (DNMT1) is an important component of the epigenetic machinery and is responsible for copying DNA methylation patterns during cell division. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming. Knockdown of DNMT1 leads to inhibition of DNA replication, but the mechanism has been unclear. Here we show that depletion of DNMT1 with either antisense or small interfering RNA (siRNA) specific to DNMT1 activates a cascade of genotoxic stress checkpoint proteins, resulting in phosphorylation of checkpoint kinases 1 and 2 (Chk1 and -2), gammaH2AX focus formation, and cell division control protein 25a (CDC25a) degradation, in an ataxia telangiectasia mutated-Rad3-related (ATR)-dependent manner. siRNA knockdown of ATR blocks the response to DNMT1 depletion; DNA synthesis continues in the absence of DNMT1, resulting in global hypomethylation. Similarly, the response to DNMT1 knockdown is significantly attenuated in human mutant ATR fibroblast cells from a Seckel syndrome patient. This response is sensitive to DNMT1 depletion, independent of the catalytic domain of DNMT1, as indicated by abolition of the response with ectopic expression of either DNMT1 or DNMT1 with the catalytic domain deleted. There is no response to short-term treatment with 5-aza-deoxycytidine (5-aza-CdR), which causes demethylation by trapping DNMT1 in 5-aza-CdR-containing DNA but does not cause disappearance of DNMT1 from the nucleus. Our data are consistent with the hypothesis that removal of DNMT1 from replication forks is the trigger for this response.

Animals↗

PubMed2004

Abnormal response to metabolic stress in schizophrenia: marker of vulnerability or acquired sensitization?

BACKGROUND: Previous work suggests that individuals with schizophrenia display an altered homovanillic acid (HVA) response to metabolic stress. The present study replicated and extended this paradigm, including individuals with elevated genetic risk for schizophrenia. METHOD: Patients with psychosis (n = 50), non-psychotic first-degree relatives of patients with psychosis (n = 51) and controls without psychosis (n = 50) underwent, in randomized order, double-blind administration of placebo and the glucose analogue 2-deoxy-D-glucose (2DG), which induces a mild, transient clinical state of glucoprivation. Plasma HVA and cortisol were assessed twice before the start of the 2DG/placebo infusion (baseline values), as well as four times post infusion. Data were analysed using multi-level random regression techniques. RESULTS: During the stress condition, significant increases in plasma HVA and cortisol were found. The increase in plasma HVA level during the stress condition was significantly stronger in patients than in controls, whereas this was not the case in relatives v. controls. The increase in plasma cortisol during the stress condition was significantly less in patients than controls, but no significant difference in the increase of plasma cortisol during stress was found in the comparison between relatives and controls. CONCLUSIONS: Patients with psychosis, but not their non-psychotic first-degree relatives, show an altered neurobiological response to metabolic stress, suggesting that this dysregulation is not a genetically transmitted vulnerability, but an illness-related effect, possibly reflecting acquired sensitization of neuroendocrine systems by repeated environmental stressors or repeated stimulation with agonistic drugs.

Adolescent↗

PubMed2000

Stress response genes: the genes that make cancer metastasize.

Cancer is characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. The topology of cancer spread is mediated by a set of developmentally nonessential genes which are physiologically involved in stress responses, inflammation, wound healing, and neovascularization. The function of these gene products is extensively modified posttranscriptionally. In cancer, metastasis genes are dysregulated at the levels of expression or splicing. These genes constitute a unique group of cancer-related biomolecules.

Animals↗

PubMed2006

Deep senescent human fibroblasts show diminished DNA damage foci but retain checkpoint capacity to oxidative stress.

Critically shortened telomeres trigger a DNA damage response in replicatively senescent cells. Here we report that while DNA damage foci can be detected in newly senescent cells, these foci eventually diminished in deep senescent cells. However, DNA checkpoint signalling and repair machinery in response to oxidative stress remain uncompromised in these deep senescent cells. Activation of p53 by oxidative stress is unaffected despite a marked decrease in expression of platelet-derived growth factor alpha-receptor. These findings suggest that cellular senescence is not a static process hence care must be taken in the selection of biomarkers of senescence in studies of ageing.

Cell Proliferation↗

PubMed1975

The role of information in attenuating behavioral responses to stress: a reinterpretation of the misattribution phenomenon.

Two experiments replicating and extending Ross, Rodin, and Zimbardo were conducted to determine whether reductions in emotional behavior resulted from misattribution of naturally occurring arousal states or from informational factors confounded in previous research. In Experiment 1, arousal or arousal-irrelevant symptoms were attributed to noise or the threat of shock. Subjects receiving arousal symptoms avoided shock less, regardless of attribution. Extended manipulation checks revealed no evidence of differential attribution of arousal. In Experiment 2 subjects heard high or low noise. Arousal symptoms were attributed to noise or threat of shock. Subjects for whom arousal symptoms were attributed to noise and who heard low noise spent more time in shock avoidance than the other three groups. Again there was no evidence of misattribution of arousal. The results are interpreted as indicating that the results of misattribution studies are best explained in terms of the presentation of arousal information in a plausible context.

Arousal↗

PubMed2004

Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses.

We have undertaken a global analysis of sumoylated proteins in Saccharomyces cerevisiae by tandem mass spectrometry. Exposure of cells to oxidative and ethanol stresses caused large increases in protein sumoylation. A large number of new sumoylated proteins were identified in untreated, hydrogen peroxide-treated, and ethanol-treated cells. These proteins are known to be involved in diverse cellular processes, including gene transcription, protein translation, DNA replication, chromosome segregation, metabolic processes, and stress responses. Additionally, the known enzymes, including E1, E2, and E3 of the sumoylation cascade were found to be auto-sumoylated. Taken together, these results show that protein sumoylation is broadly involved in many cellular functions and this mass spectrometry-based proteomic approach is useful in studying the regulation of protein sumoylation in the cells.

Blotting, Western↗

PubMed1998

Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.

In response to DNA damage and replication blocks, cells prevent cell cycle progression through the control of critical cell cycle regulators. We identified Chk2, the mammalian homolog of the Saccharomyces cerevisiae Rad53 and Schizosaccharomyces pombe Cds1 protein kinases required for the DNA damage and replication checkpoints. Chk2 was rapidly phosphorylated and activated in response to replication blocks and DNA damage; the response to DNA damage occurred in an ataxia telangiectasia mutated (ATM)-dependent manner. In vitro, Chk2 phosphorylated Cdc25C on serine-216, a site known to be involved in negative regulation of Cdc25C. This is the same site phosphorylated by the protein kinase Chk1, which suggests that, in response to DNA damage and DNA replicational stress, Chk1 and Chk2 may phosphorylate Cdc25C to prevent entry into mitosis.

Amino Acid Sequence↗

PubMed2005

Protein synthesis in eukaryotes: the growing biological relevance of cap-independent translation initiation.

Ribosome recruitment to eukaryotic mRNAs is generally thought to occur by a scanning mechanism, whereby the 40S ribosomal subunit binds in the vicinity of the 5'cap structure of the mRNA and scans until an AUG codon is encountered in an appropriate sequence context. Study of the picornaviruses allowed the characterization of an alternative mechanism of translation initiation. Picornaviruses can initiate translation via an internal ribosome entry segment (IRES), an RNA structure that directly recruits the 40S ribosomal subunits in a cap and 5' end independent fashion. Since its discovery, the notion of IRESs has extended to a number of different virus families and cellular RNAs. This review summarizes features of both cap-dependent and IRES-dependent mechanisms of translation initiation and discusses the role of cis-acting elements, which include the 5' cap, the 5'-untranslated region (UTR) and the poly(A) tail as well as the possible roles of IRESs as part of a cellular stress response mechanism and in the virus replication cycle.

5' Untranslated Regions↗

PubMed2002

Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts.

A stress-induced senescence-like phenotype is induced by exposure of human diploid fibroblasts to subcytotoxic H2O2 stress. Previous studies showed that TGF-beta1 is responsible for the induction of several biomarkers of replicative senescence within 72 h after stress: senescence-like morphology, senescence-associated beta-galactosidase activity, and an increase in the mRNA steady state level of four senescence-associated genes. Other studies showed that the retinoblastoma protein is responsible for the appearance of these biomarkers in the same conditions. Here we show that sustained p38(MAPK) phosphorylation is responsible for both H2O2-induced overexpression of TGF-beta 1 and subsequent TGF-beta 1-induced appearance of these biomarkers. p38(MAPK) phosphorylation is shown to be necessary for a self-sustained TGF-beta 1 overexpression after H2O2 stress through the activation of ATF-2 transcription factor, thereby creating a regulatory loop between sustained p38(MAPK) activation and sustained TGF-beta 1 overexpression after stress. p38(MAPK) activation is also shown to be responsible in part for the growth arrest observed in stress-induced senescence-like phenotype. At 48 h after stress, ATF-2 starts to interact with hypophosphorylated Rb, which allows the biomarkers of stress-induced senescence-like phenotype to appear. This report gives an overall explanation of how a senescence-like phenotype is established after subcytotoxic H2O2 stress.

Activating Transcription Factor 2↗

PubMed1993

Cell and tissue responses to oxidative damage.

A broad array of oxidative stresses modulates gene expression in a variety of mammalian cells. One goal of this review was to characterize cellular responses to oxidative injury, how these processes are regulated, and the outcome for a particular cell or tissue. Many genes induced in response to specific oxidant stresses have been identified and include transcription factors, replication proteins, proteases, protease inhibitors, proteins affecting cell proliferation and various antioxidants, i.e. heme oxygenase, MT, and MnSOD. The latter enzyme is induced after a number of cytokines and oxidant stresses including hyperoxia and mineral dusts causing inflammation. Moreover, increases in mRNA levels of TNF and IL-1, cytokines inducing MnSOD, are observed after exposure to UV and ionizing radiation. Since increased electron flow could lead to generation of more AOS within mitochondria, increased levels of MnSOD might be necessary to maintain normal functioning of the mitochondria after oxidative stress. Alterations in cell growth are intrinsically related to the pathogenesis of many diseases. Paradoxically, some of the responses of cells to oxidative stress reflect cytotoxicity and cytostasis, whereas others result in increased cell proliferation. For example, induction of gadd genes observed after oxidative stress is related to growth arrest of cells, a response which might enable the cell to repair oxidative damage prior to replication. This phenomenon might prevent fixation of mutations associated with oxidative DNA damage. On the other hand, increased mRNA expression and activity of ODC, observed after exposure of cells to UV or asbestos is associated with increased cell proliferation. In addition, increased mRNA expression of cellular proto-oncogenes observed after exposure to oxidants could also be related to increased DNA synthesis or proliferation. Figure 5 provides a general scheme of cell responses to oxidative stress and possible ramifications. AOS can react with a number of target molecules including proteins, lipids, and DNA. These interactions elicit a number of signals including activation of gene regulatory factors (transcription factors) which in turn activate oxidative stress-responsive genes or regulons. Consequently, a number of proteins are produced with distinctive functions including DNA repair enzymes, antioxidants, proteases inhibitors, cytokines and proteins affecting cell proliferation. These cellular responses to AOS can lead to restoration of normal cellular function and adaptation to oxidative stress, cell death or aberrant proliferation. It is the latter two responses which can lead to a variety of disease states including cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts.

In addition to replicative senescence, normal diploid fibroblasts undergo stress-induced premature senescence (SIPS) in response to DNA damage caused by oxidative stress or ionizing radiation (IR). SIPS is not prevented by telomere elongation, indicating that, unlike replicative senescence, it is triggered by nonspecific genome-wide DNA damage rather than by telomere shortening. ATM, the product of the gene mutated in individuals with ataxia telangiectasia (AT), plays a central role in cell cycle arrest in response to DNA damage. Whether ATM also mediates signaling that leads to SIPS was investigated with the use of normal and AT fibroblasts stably transfected with an expression vector for the catalytic subunit of human telomerase (hTERT). Expression of hTERT in AT fibroblasts resulted in telomere elongation and prevented premature replicative senescence, but it did not rescue the defect in G(1) checkpoint activation or the hypersensitivity of the cells to IR. Despite these remaining defects in the DNA damage response, hTERT-expressing AT fibroblasts exhibited characteristics of senescence on exposure to IR or H(2)O(2) in such a manner that triggers SIPS in normal fibroblasts. These characteristics included the adoption of an enlarged and flattened morphology, positive staining for senescence-associated beta-galactosidase activity, termination of DNA synthesis, and accumulation of p53, p21(WAF1), and p16(INK4A). The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which mediates signaling that leads to senescence, was also detected in both IR- or H(2)O(2)-treated AT and normal fibroblasts expressing hTERT. These results suggest that the ATM-dependent signaling pathway triggered by DNA damage is dispensable for activation of p38 MAPK and SIPS in response to IR or oxidative stress.

Ataxia Telangiectasia↗

PubMed2006

Temporal transcriptomic analysis as Desulfovibrio vulgaris Hildenborough transitions into stationary phase during electron donor depletion.

Desulfovibrio vulgaris was cultivated in a defined medium, and biomass was sampled for approximately 70 h to characterize the shifts in gene expression as cells transitioned from the exponential to the stationary phase during electron donor depletion. In addition to temporal transcriptomics, total protein, carbohydrate, lactate, acetate, and sulfate levels were measured. The microarray data were examined for statistically significant expression changes, hierarchical cluster analysis, and promoter element prediction and were validated by quantitative PCR. As the cells transitioned from the exponential phase to the stationary phase, a majority of the down-expressed genes were involved in translation and transcription, and this trend continued at the remaining times. There were general increases in relative expression for intracellular trafficking and secretion, ion transport, and coenzyme metabolism as the cells entered the stationary phase. As expected, the DNA replication machinery was down-expressed, and the expression of genes involved in DNA repair increased during the stationary phase. Genes involved in amino acid acquisition, carbohydrate metabolism, energy production, and cell envelope biogenesis did not exhibit uniform transcriptional responses. Interestingly, most phage-related genes were up-expressed at the onset of the stationary phase. This result suggested that nutrient depletion may affect community dynamics and DNA transfer mechanisms of sulfate-reducing bacteria via the phage cycle. The putative feoAB system (in addition to other presumptive iron metabolism genes) was significantly up-expressed, and this suggested the possible importance of Fe2+ acquisition under metal-reducing conditions. The expression of a large subset of carbohydrate-related genes was altered, and the total cellular carbohydrate levels declined during the growth phase transition. Interestingly, the D. vulgaris genome does not contain a putative rpoS gene, a common attribute of the delta-Proteobacteria genomes sequenced to date, and the transcription profiles of other putative rpo genes were not significantly altered. Our results indicated that in addition to expected changes (e.g., energy conversion, protein turnover, translation, transcription, and DNA replication and repair), genes related to phage, stress response, carbohydrate flux, the outer envelope, and iron homeostasis played important roles as D. vulgaris cells experienced electron donor depletion.

Bacterial Proteins↗

PubMed1997

Attenuated stress responses in young and old human lymphocytes.

Aging generally is understood to be a period defined by altered responses to physiological stress. At the molecular level, several stress responses involving specific gene expression have been revealed, and thermal stress has been tightly linked to induction of the heat shock gene family (D.A. Jurivich. In E. Bittar (ed.), Principles of Medical Biology, Vol. 4, JAI press, San Diego, 1996, pp. 411-462). Perturbations in heat shock gene transcription consistently have been noted in senescent cells from all species examined thus far. Because heat shock proteins serve several vital functions in the immune system, changes in the thermal stress response could potentially contribute to immunosenescence. Inadequate promoter priming by the transactivator or heat shock genes, heat shock factor 1 (HSF1), is thought to account for age-dependent diminution in expression of these genes, although the exact mechanism for this loss is not clearly understood. We have found that human lymphocytes exhibit an age-dependent loss in HSF1-DNA binding, although a range of binding has been observed in both young and old donor cells. This report characterizes a subset of young and old human donor lymphocytes that are non-responders to thermal stress defined by the absence of HSF1-DNA binding after a 42 degrees C heat shock. Whole cell extracts from these donor cells have the capacity to inhibit HSF1-DNA binding when mixed with pre-activated HSF1 from HeLa cells. This inhibitory activity is lost upon heat denaturation and does not appear to be protease mediated. Serial passage of lymphoblasts recapitulates loss of heat inducible HSF1-DNA observed in old donor lymphocytes, thus suggesting that loss of replicative potential and aging lead to altered stress responses. Uncoupling of the thermal response and its potential relevance to apoptosis and aging are discussed.

Adult↗