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At least 19 recordsLinked to original sources
PubMed2000

Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease.

Huntington's disease (HD), spinocerebellar ataxias types 1 and 3 (SCA1, SCA3), and spinobulbar muscular atrophy (SBMA) are caused by CAG/polyglutamine expansion mutations. A feature of these diseases is ubiquitinated intraneuronal inclusions derived from the mutant proteins, which colocalize with heat shock proteins (HSPs) in SCA1 and SBMA and proteasomal components in SCA1, SCA3, and SBMA. Previous studies suggested that HSPs might protect against inclusion formation, because overexpression of HDJ-2/HSDJ (a human HSP40 homologue) reduced ataxin-1 (SCA1) and androgen receptor (SBMA) aggregate formation in HeLa cells. We investigated these phenomena by transiently transfecting part of huntingtin exon 1 in COS-7, PC12, and SH-SY5Y cells. Inclusion formation was not seen with constructs expressing 23 glutamines but was repeat length and time dependent for mutant constructs with 43-74 repeats. HSP70, HSP40, the 20S proteasome and ubiquitin colocalized with inclusions. Treatment with heat shock and lactacystin, a proteasome inhibitor, increased the proportion of mutant huntingtin exon 1-expressing cells with inclusions. Thus, inclusion formation may be enhanced in polyglutamine diseases, if the pathological process results in proteasome inhibition or a heat-shock response. Overexpression of HDJ-2/HSDJ did not modify inclusion formation in PC12 and SH-SY5Y cells but increased inclusion formation in COS-7 cells. To our knowledge, this is the first report of an HSP increasing aggregation of an abnormally folded protein in mammalian cells and expands the current understanding of the roles of HDJ-2/HSDJ in protein folding.

Acetylcysteine↗
PubMed2002

Drought acclimation and lipid composition in Folsomia candida: implications for cold shock, heat shock and acute desiccation stress.

Many of the physiological adaptations evolved in terrestrial invertebrates to resist desiccation have also been shown to enhance the survival of low temperatures. In this study we have examined temporal changes in the physiology of the collembolan Folsomia candida during acclimation to mild desiccation stress (98.2% RH), and how physiological changes correlate with resistance to subsequent cold shock, heat shock and acute desiccation stress. Drought-acclimation increased the resistance to cold and acute drought but reduced the resistance to heat shock. The composition of membrane phospholipid fatty acids (PLFA) changed during acclimation resulting in a higher degree of unsaturation by the end of the 192-h acclimation period. This resembles typical membrane alterations seen in ectothermic animals exposed to cold. Only small changes were seen in the neutral lipid fraction. The temporal changes in cold resistance and drought resistance correlated well with changes in PLFA composition and accumulation of sugars and polyols ('cryoprotectives'). It is proposed that the drought-induced PLFA desaturation, combined with the membrane protecting accumulation of cryoprotectives, are important physiological adaptations providing tolerance to both desiccation and cold.

Journal Article↗
PubMed1994

Fine structure analyses of the Drosophila and Saccharomyces heat shock factor--heat shock element interactions.

Heat shock genes are activated by the binding of the heat shock transcription factor (HSF) to heat shock elements (HSEs), consisting of arrays of the 5-bp unit NGAAN arranged as inverted repeats. Here, we have investigated the interaction of the 5-bp unit with HSFs of Drosophila and Saccharomyces. Mutations within the conserved, central trinucleotide GAA reduce the relative binding affinity of both HSFs. In addition, the base at position 1 (N1) also influences binding, with a strong preference for an A at this position. Methylation interference initially indicated that HSF contacts A1 in the minor groove, but interacts with the immediately adjacent base G2 in the major groove. Further characterization of this apparently abrupt minor to major groove transition by substitution of A1 with an inosine, shows that HSF contacts A1 in the major groove. We offer an explanation for this apparent contradiction and propose that HSF recognizes the HSE primarily through contacts within the major groove of the DNA helix. Finally, based on these observations and a re-evaluation of the base frequencies and criteria for consensus sequence assignment, we propose that the sequence AGAAN more accurately represents the consensus HSE motif.

Animals↗
PubMed2001

Heat shock and heat shock protein 70i enhance the oncolytic effect of replicative adenovirus.

Replication-competent viruses are currently being evaluated for their cancer cell-killing properties. These vectors are designed to induce tumor regression after selective viral propagation within the tumor. However, replication-competent viruses have not resulted heretofore in complete tumor eradication in the clinical setting. Recently, heat shock has been reported to partially alleviate replication restriction on an avian adenovirus (Ad) in a human lung cancer cell line. Therefore, we hypothesized that heat shock and overexpression of heat shock protein (hsp) would support the oncolytic effect of a replication-competent human Ad. To this end, we tested the oncolytic and burst kinetics of a replication-competent Ad after exposure to heat shock or to inducible hsp 70 overexpression by a replication-deficient Ad (Adhsp 70i). Heat-shock resulted in augmentation of Ad burst and oncolysis while decreasing total intracellular Ad DNA. Overexpression of hsp 70i also enhanced Ad-mediated oncolysis but did not decrease intracellular Ad DNA levels. We conclude that heat shock and Adhsp 70i enhance the Ad cell-killing potential via distinct mechanisms. A potential therapeutic implication would be the use of local hyperthermia to augment oncolysis by increasing the burst of replication-competent Ad. The role of hsp in Ad-mediated oncolysis should be additionally explored.

Adenoviruses, Human↗
PubMed2006

Protective role of heat shock and heat shock protein 70 in lactacystin-induced cell death both in the rat substantia nigra and PC12 cells.

Proteasomal dysfunction plays an important role in the pathogenesis of Parkinson disease (PD). Although clinical and experimental evidence continues to accumulate indicating heat shock protein 70 (HSP70) is significant in the pathogenesis of PD, few studies have been made to investigate the role of HSP70 under the condition of proteasome dysfunction. In in vivo study, we infused lactacystin into the unilateral substantia nigra (SN) of Sprague-Dawley rats with or without preceding whole body hyperthermia (WBH). Immunohistochemical studies showed the death of dopaminergic neurons and activated microglia in the SN. Lactacystin with prior WBH increased the expression of HSP70 more than did lactacystin alone and decreased lactacystin-induced dopaminergic neuronal death in the SN. In PC12 cells, heat shock pretreatment decreased lactacystin-induced cell death. Although additional treatment of nocodazole, ammonium chloride, and 3-methyladenine augmented cell death by lactacystin, heat shock pretreated to these drugs offsets their additional toxicity. These results indicate that heat shock proteins, especially HSP70, could play an important role under the condition of proteasome dysfunction in part by fostering aggresome formation and lysosome-mediated autophagy.

Acetylcysteine↗
PubMedDate not supplied

Heat shock response, heat shock transcription factor and cell aging.

A characteristic feature of aging is a progressive impairment in the ability to adapt to environmental challenges. The purpose of this article is to review the evidence of an attenuated response to heat and physiological stresses in a number of mammalian aging model systems, including the human diploid fibroblasts in culture, whole animals and animal-derived cells and cell cultures, as well as peripheral blood mononuclear cells obtained from human donors. Analyses of the regulation and function of heat shock factor 1 (HSF1), a transcription factor that mediates the response to heat shock, showed that while the relative abundance of both the hsf1 transcript and the HSF1 protein did not change as a function of age, the responsiveness of HSF1 to heat-induced activation, as measured by its trimerization and ability to bind to the heat shock element consensus sequence, was inversely related to the age of the cells used. Given the fundamentally important role of heat shock proteins (HSPs) in many aspects of protein homeostasis and signal transduction it seems likely that the inability, or compromised ability, of aging cells and organisms to activate HSF1 and produce HSPs in response to stress would contribute to the well-known increase in morbidity and mortality of the aged when challenged.

Aging↗
PubMed1996

Distinctive immunohistochemical profiles of small heat shock proteins (heat shock protein 27 and alpha B-crystallin) in human brain tumors.

BACKGROUND: Recent studies have described alpha B-crystallin as a member of the small heat shock protein (HSP) family, and the expressions of alpha-crystallin-related small heat shock proteins, namely HSP27 and alpha B-crystallin, in the brain appear to be regulated in a similar way by various stress conditions. METHODS: A comparative immunohistochemical analysis was performed on 198 human brain tumors to examine the expressions of HSP27 and alpha B-crystallin. RESULTS: Positive staining with HSP27 was frequently observed in schwannomas, craniopharyngiomas, epidermoid cysts, and metastatic tumors to the brain. The immunopositivity of HSP27 was relatively low in tumors originating from neuroepithelium as well as in meningiomas; however, a statistically significantly higher percentage of HSP27-positive cells was noted in their anaplastic counterparts, such as glioblastomas, anaplastic oligodendrogliomas, anaplastic ependymomas, and anaplastic meningiomas (P < 0.005). Conversely, a positive immunoexpression of alpha B-crystallin was frequently observed among astrocytic tumors, schwannomas, hemangioblastomas, and chordomas. CONCLUSIONS: The immunohistochemical expression of HSP27 and alpha B-crystallin differed among histologic types of tumors. Furthermore, the immunopositivity of HSP27, which was considered to play a role not only in drug resistance but also in the regulation of cell proliferation, increased in proportion to the anaplasia of the tumors.

Astrocytoma↗
PubMed2002

Invited review: Interplay between molecular chaperones and signaling pathways in survival of heat shock.

Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.

Animals↗
PubMed2002

Apoptosis is an adaptive response in bovine preimplantation embryos that facilitates survival after heat shock.

Heat shock compromises development of preimplantation bovine embryos and the percentage of blastomeres labeled as TUNEL-positive. It was hypothesized that TUNEL labeling represents apoptosis and that apoptosis after heat shock is beneficial for continued embryonic development. To test these hypotheses, experiments were performed with z-DEVD-fmk, an inhibitor of group II caspases, on heat shock responses of embryos > or =16-cell stage at day 4 after insemination. Heat shock of 41 degrees C for 9 h increased group II caspase activity and the proportion of TUNEL positive cells; z-DEVD-fmk blocked these effects. The reduction in development of embryos exposed to heat shock for 6-9 h was magnified in the presence of z-DEVD-fmk. Results indicate that group II caspases mediate heat-induced apoptosis in bovine embryos and that inhibition of these caspases has a detrimental effect on embryonic resistance to heat shock. Apoptosis can be viewed as an adaptative mechanism to allow embryonic survival and development following stress.

Adaptation, Physiological↗
PubMed1994

Improved postischemic ventricular functional recovery by amphetamine is linked with its ability to induce heat shock.

Heat shock has been shown to increase the cellular tolerances to ischemic injury. In this study, we examined the effects of heat shock induced by amphetamine on postischemic myocardial functional recovery in a setting of coronary revascularization for acute myocardial infarction. Intramuscular injection of amphetamine (3 mg/kg, i.m.) to pigs increased the body temperature to 42.5 degrees C within 1 h, and maintained this temperature for an additional 2 h. Fourty h after the amphetamine injection, the pigs were placed on by cardiopulmonary bypass and then isolated, in situ heart preparations were subjected to 1 h of global hypothermic cardioplegic arrest and 1 h of normothermic reperfusion. Postischemic myocardial performance was monitored by measuring left ventricular (LV) pressure, its dp/dt, myocardial segmental shortening (%SS), and coronary blood flow. Cellular injury was examined by measuring creatine kinase (CK) release. Biochemical measurements included quantification of plasma catecholamines and study of the induction of heat shock gene expression and antioxidative enzymes in the heart tissue. The results of this study indicated significantly greater recovery of LV contractile functions by amphetamine as demonstrated by improved recovery of LVDP (61% vs 52%), dp/dtmax (52% vs 44%), and segmental shortening (46.2% vs 10%). Myocardial CK release was significantly reduced in the amphetamine group. Furthermore, amphetamine pretreatment was associated with the induction of heat shock protein (HSP) 27 mRNA and stimulated Cu/Zn-superoxide dismutase and catalase levels, suggesting that amphetamine mediated improved postischemic ventricular recovery might be linked with its ability to induce heat shock and stimulate antioxidant enzymes.

Amphetamine↗
PubMed1991

Response of Escherichia coli cell membranes to induction of lambda cl857 prophage by heat shock.

Heat shock induces protein aggregation in Escherichia coli and E. coli (lambda cl857). The aggregates (S fraction) appear 15 min post-induction and are separable from membranes by sucrose density-gradient centrifugation. The S fraction quickly disappears in wild type strains but persists in rpoH mutant with concomitant quick inner membrane destruction. We propose that: (1) the disappearance of the S fraction reflects a rpoH-dependent processing, (2) the membrane destruction explains the lethality of the rpoH mutation at elevated temperatures; and (3) the protection of the inner membrane integrity is an important physiological function of the heat-shock response. We assume that the S fraction of aggregated proteins represents the signal inducing the heat-shock response. The prophage thermo-induction results in an increase (35 min post-induction) in the A fraction resembling that of the adhesion zones of the membranes. This fraction is greater than the corresponding fraction from uninduced cells. The increase is mediated by the lambda late genes, since it is absent in the induced E. coli (lambda cl857 Qam21). Since heat shock is widely used for induction of the lambda promoters in expression vectors it is possible that the formation of the protein aggregates (though transient in WT strains) and/or the fragility of membranes in rpoH mutants may be the cause of poor expression of cloned genes or may lead to mistaken localization of their expression products.

Bacterial Outer Membrane Proteins↗
PubMed2000

Interaction of the Neurospora crassa heat shock factor with the heat shock element during heat shock and different developmental stages.

The interaction of the heat shock factor (HSF) with the heat shock element (HSE) was determined by a non-radioactive electrophoretic mobility shift assay, in order to analyze HSF regulation in Neurospora crassa. HSF binds to HSE under normal, non-stress conditions and is thus constitutively trimerized. Upon heat shock, the HSF-HSE complex shows a retarded mobility. This was also observed in Saccharomyces cerevisiae, where this mobility shift was shown to be due to HSF phosphorylation [Sorger and Pelham (1988) Cell 54, 855-864]. In N. crassa, HSE-dependent electrophoretic mobility shift is temperature- and time-dependent. Under normal growth conditions, the HSF is located in the cytoplasm as well as in the nucleus. In germinating conidia the HSF shows a retarded mobility typical for heat shock even at normal growth temperatures. No HSF-dependent mobility shift was detectable in aerial hyphae.

DNA-Binding Proteins↗
PubMed2003

Transcriptional activation of a constitutive heterochromatic domain of the human genome in response to heat shock.

Heat shock triggers the assembly of nuclear stress bodies that contain heat shock factor 1 and a subset of RNA processing factors. These structures are formed on the pericentromeric heterochromatic regions of specific human chromosomes, among which chromosome 9. In this article we show that these heterochromatic domains are characterized by an epigenetic status typical of euchromatic regions. Similarly to transcriptionally competent portions of the genome, stress bodies are, in fact, enriched in acetylated histone H4. Acetylation peaks at 6 h of recovery from heat shock. Moreover, heterochromatin markers, such as HP1 and histone H3 methylated on lysine 9, are excluded from these nuclear districts. In addition, heat shock triggers the transient accumulation of RNA molecules, heterogeneous in size, containing the subclass of satellite III sequences found in the pericentromeric heterochromatin of chromosome 9. This is the first report of a transcriptional activation of a constitutive heterochromatic portion of the genome in response to stress stimuli.

Acetylation↗
PubMed2001

Mutation of amino acids 566-572 (KKKVLDK) inhibits nuclear accumulation of heat shock protein 72 after heat shock.

Heat shock protein (HSP) 72 translocates from the cytoplasm to the nucleus in response to a wide variety of stresses, including heat shock and tissue ischemia. It is thought that this concentration of HSP72 in the nucleus with stress is part of the protein's protective response. Therefore, further understanding of the regulation of this response would be of interest. The signals regulating HSP72's nuclear localization have not been completely defined. Previously, we observed that mutation of amino acids 246-251 (KRKHKK) reduced nuclear accumulation of HSP72 and that a KRKHKK-EGFP (enhanced green fluorescent protein) fusion protein concentrated in the nucleoli. In examining HSP72 for other potential nuclear localization signals, we identified an additional sequence, KKKVLDK, amino acids 566-572, that might effect nuclear accumulation. We now report that mutation of KKKVLDK inhibited nuclear concentration of HSP72 following heat shock, and the fusion protein KKKVLDK-EGFP concentrated in the nucleus. Cells overexpressing the KKKVLDK mutant showed reduced resistance to heat shock. Mutation of KKKVLDK and KRKHKK abolished nuclear accumulation of HSP72 and reduced cell viability following heat shock to a greater extent than mutation of either site alone. These findings suggest that these two sequences, KRKHKK and KKKVLDK, have complementary function(s) in cellular protection after heat shock.

Adenosine Triphosphate↗
PubMed2000

RSK2 represses HSF1 activation during heat shock.

Heat shock transcription factor 1(HSF1) activation is a multistep process. The conversion of a latent cytoplasmic form to a nuclear, DNA binding state appears to be activated by nonsteroidal anti-inflammatory drugs. In previous studies, we showed that HSF 1 is phosphorylated by the protein kinase RSK2 in vitro and that this effect is inhibited by nonsteroidal anti-inflammatory drugs at the concentration that leads to the activation of HSF1 in vivo (Stevenson et al 1999). In the present study, using cells from a patient with Coffin-Lowry syndrome (deficient in RSK2), we demonstrate that RSK2 slightly represses activation of HSF1 in vivo at 37 degrees C. In Coffin-Lowry syndrome cells, HSF1-HSE DNA binding activity after treatment with sodium salicylate was slightly higher than that in untreated cells, indicating that although RSK2 is involved in HSF1 regulation, it is not the unique protein kinase that suppresses HSF1-HSE binding activity at 37 degrees C. However, heat shock treatment resulted in significantly higher HSF1-HSE binding activity in Coffin-Lowry syndrome cells as compared with normal controls, suggesting that RSK2 represses HSF1-HSE binding activity during heat shock.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Rapid changes in Drosophila transcription after an instantaneous heat shock.

Heat shock rapidly activates expression of some genes and represses others. The kinetics of changes in RNA polymerase distribution on heat shock-modulated genes provides a framework for evaluating the mechanisms of activation and repression of transcription. Here, using two methods, we examined the changes in RNA polymerase II association on a set of Drosophila genes at 30-s intervals following an instantaneous heat shock. In the first method, Drosophila Schneider line 2 cells were quickly frozen to halt transcription, and polymerase distribution was analyzed by a nuclear run-on assay. RNA polymerase transcription at the 5' end of the hsp70 gene could be detected within 30 to 60 s of induction, and by 120 s the first wave of polymerase could already be detected near the 3' end of the gene. A similar rapid induction was found for the small heat shock genes (hsp22, hsp23, hsp26, and hsp27). In contrast to this rapid activation, transcription of the histone H1 gene was found to be rapidly repressed, with transcription reduced by approximately 90% within 300 s of heat shock. Similar results were obtained by an in vivo UV cross-linking assay. In this second method, cell samples removed at 30-s intervals were irradiated with 40-microseconds bursts of UV light from a Xenon flash lamp, and the distribution of polymerase was examined by precipitating UV cross-linked protein-DNA complexes with an antibody to RNA polymerase II. Both approaches also showed the in vivo rate of movement of the first wave of RNA polymerase through the hsp70 gene to be approximately 1.2 kb/min.

Animals↗
PubMed1988

Methylation of Drosophila histones at proline, lysine, and arginine residues during heat shock.

Heat shock or arsenite treatment alter the pattern of histone methylation in Drosophila cells. Both types of stress induce a rapid increase in the methylation level of histone H2B. The methylated amino acid residue of H2B has been identified by thin layer chromatography and electrophoresis as methylproline and is located at the N-terminal end of H2B. Heat shock also induces a decrease in the level of methylation of histone H3. Under normal growth temperature conditions, histone H3 is shown to be methylated on lysine residues. However under heat shock conditions, there is a decrease in the extent of methylation of lysine residues and the appearance of new methylation on arginine residues in H3. These new heat shock-induced methylated residues have been identified as the symmetrical and asymmetrical forms of dimethylarginine. The methylated amino acid residue of histone H4 is lysine with mono-, di-, and trimethyl forms found in both control and heat or chemically stressed cells. These stress-induced changes in the methylation level of the N-terminal proline residue of histone H2B and shift in the methylation sites of histone H3 may be involved in the restructuration of chromatin accompanying the inactivation of normal genes in response to stress. Moreover, we suggest that the hypermethylation of H2B may also be involved in its protection from increased ubiquitin-mediated proteolytic activity under these conditions of cellular stress.

Amino Acids↗