Showing papers on "Heat shock protein published in 2013"
TL;DR: The structural basis of their mechanism of action is being unravelled and typically involves massive displacements of 20–30 kDa domains over distances of 20-50 Å and rotations of up to 100°.
Abstract: Molecular chaperones are diverse families of multidomain proteins that have evolved to assist nascent proteins to reach their native fold, protect subunits from heat shock during the assembly of complexes, prevent protein aggregation or mediate targeted unfolding and disassembly. Their increased expression in response to stress is a key factor in the health of the cell and longevity of an organism. Unlike enzymes with their precise and finely tuned active sites, chaperones are heavy-duty molecular machines that operate on a wide range of substrates. The structural basis of their mechanism of action is being unravelled (in particular for the heat shock proteins HSP60, HSP70, HSP90 and HSP100) and typically involves massive displacements of 20–30 kDa domains over distances of 20–50 A and rotations of up to 100°.
824 citations
TL;DR: The history, regulation, mechanism of action and role in cancer of the HSP70 family are reviewed, and the promise of pharmacologically targeting this protein for cancer therapy is addressed.
Abstract: The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascently translating proteins, promote the cellular or organellar transport of proteins, reduce proteotoxic protein aggregates and serve general housekeeping roles in maintaining protein homeostasis. The HSP70 family is the most conserved in evolution, and all eukaryotes contain multiple members. Some members of this family serve specific organellar- or tissue-specific functions; however, in many cases, these members can function redundantly. Overall, the HSP70 family of proteins can be thought of as a potent buffering system for cellular stress, either from extrinsic (physiological, viral and environmental) or intrinsic (replicative or oncogenic) stimuli. As such, this family serves a critical survival function in the cell. Not surprisingly, cancer cells rely heavily on this buffering system for survival. The overwhelming majority of human tumors overexpress HSP70 family members, and expression of these proteins is typically a marker for poor prognosis. With the proof of principle that inhibitors of the HSP90 chaperone have emerged as important anticancer agents, intense focus has now been placed on the potential for HSP70 inhibitors to assume a role as a significant chemotherapeutic avenue. In this review, the history, regulation, mechanism of action and role in cancer of the HSP70 family are reviewed. Additionally, the promise of pharmacologically targeting this protein for cancer therapy is addressed.
466 citations
TL;DR: This review describes the different molecules and approaches being used or proposed in cancer therapy based on the in inhibition of HSP90, HSP70 and HSP27.
407 citations
TL;DR: Recent insights into the structure and mechanism of Hsp70s are discussed, shedding light on the molecular mechanism by which Hsp80s assist protein folding and suggesting that Hsp 70s exist in at least two conformational states.
380 citations
TL;DR: The current status of HSP90 inhibitors in clinical development is reviewed, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors.
Abstract: Summary Heat shock protein 90 (HSP90) is a molecular chaperone that is crucial for the stability and function of many proteins essential for cell survival. Many oncogenes, including tyrosine kinases, transcription factors, and cell-cycle regulatory proteins, are client proteins of HSP90. Inhibition of HSP90 causes client protein degradation via the ubiquitin–proteasome pathway, and is a mechanism that might simultaneously downregulate several redundant pathways crucial for cell viability and tumour development. HSP90 inhibitors are currently being developed as anticancer agents, and have shown early promising results in molecularly defined subgroups of solid tumours (eg, ALK-rearranged non-small-cell lung cancer and HER2-amplified breast cancer) and some haematological malignancies (eg, multiple myeloma). Here, we review the current status of HSP90 inhibitors in clinical development, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors. We also discuss novel strategies and future perspectives on how to optimise the therapeutic potential of this exciting new class of drugs.
309 citations
TL;DR: It is reported here that heat stress rapidly induces miR398 and reduces transcripts of its target genes CSD1, CSD2 and CCS (a gene encoding a copper chaperone for both CSD 1 and CSD 2) and that plants use a previously unrecognized strategy to achieve thermotolerance, especially for the protection of reproductive tissues.
Abstract: microRNAs (miRNAs) play important roles in plant growth and development. Previous studies have shown that down-regulation of miR398 in response to oxidative stress permits up-regulation of one of its target genes, CSD2 (copper/zinc superoxide dismutase), and thereby helps plants to cope with oxidative stress. We report here that heat stress rapidly induces miR398 and reduces transcripts of its target genes CSD1, CSD2 and CCS (a gene encoding a copper chaperone for both CSD1 and CSD2). Transgenic plants expressing miR398-resistant forms of CSD1, CSD2 and CCS under the control of their native promoters are more sensitive to heat stress (as indicated by increased damage at the whole-plant level and to flowers) than transgenic plants expressing normal coding sequences of CSD1, CSD2 or CCS under the control of their native promoters. In contrast, csd1, csd2 and ccs mutant plants are more heat-tolerant (as indicated by less damage to flowers) than the wild-type. Expression of genes encoding heat stress transcription factors (HSF genes) and heat shock proteins (HSP genes) is reduced in heat-sensitive transgenic plants expressing miR398-resistant forms of CSD1, CSD2 or CCS but is enhanced in the heat-tolerant csd1, csd2 and ccs plants. Chromatin immunoprecipitation assays revealed that HSFA1b and HSFA7b are the two HSFs responsible for heat induction of miR398. Together, our results suggest that plants use a previously unrecognized strategy to achieve thermotolerance, especially for the protection of reproductive tissues. This strategy involves the down-regulation of CSD genes and their copper chaperone CCS through heat-inducible miR398.
294 citations
TL;DR: It was observed that the overall success rate achieved by iHSP-PseRAAAC in identifying the functional types of HSPs among the aforementioned six types was more than 87%, which was derived by the jackknife test on a stringent benchmark dataset.
270 citations
TL;DR: The extensive work that has been carried out and is still in progress aimed at understanding the oncogenic mechanisms by which HSP genes are switched on, determining the roles of HSF 1/HSP in malignant transformation and discovering approaches to therapy based on disrupting the influence of the HSF1-controlled transcriptome in cancer are reviewed.
Abstract: Heat shock proteins (HSP) are a subset of the molecular chaperones, best known for their rapid and abundant induction by stress. HSP genes are activated at the transcriptional level by heat shock transcription factor 1 (HSF1). During the progression of many types of cancer, this heat shock transcriptional regulon becomes co-opted by mechanisms that are currently unclear, although evidently triggered in the emerging tumor cell. Concerted activation of HSF1 and the accumulation of HSPs then participate in many of the traits that permit the malignant phenotype. Thus, cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic. We review here the extensive work that has been carried out and is still in progress aimed at (1) understanding the oncogenic mechanisms by which HSP genes are switched on, (2) determining the roles of HSF1/HSP in malignant transformation and (3) discovering approaches to therapy based on disrupting the influence of the HSF1-controlled transcriptome in cancer.
239 citations
TL;DR: With more than 200 "client" proteins, many of them meta-stable and oncogenic, HSP90 inhibition can affect an array of tumors and lessons learned from completed clinical trials of H SP90 inhibitors are discussed.
222 citations
TL;DR: Resistance-free apoptosis-inducing magnetic nanoparticles (RAINs) successfully promote hyperthermic apoptosis, obstructing cell survival by triggering two functional units of heat generation and the release of geldanamycin for heat shock protein inhibition under an alternating magnetic field (AMF).
Abstract: Overcoming resistance: Heat-treated cancer cells possess a protective mechanism for resistance and survival. Resistance-free apoptosis-inducing magnetic nanoparticles (RAINs) successfully promote hyperthermic apoptosis, obstructing cell survival by triggering two functional units of heat generation and the release of geldanamycin (GM) for heat shock protein (Hsp) inhibition under an alternating magnetic field (AMF).
201 citations
TL;DR: Limited data indicate that proper insulin action is necessary to effectively mount a response to heat stress and minimize heat-induced damage, and nutritional interventions targeting increased insulin action may improve tolerance and productivity during heat stress.
TL;DR: The data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-Chaperone expression and chaperone modifications.
Abstract: Heat shock proteins Hsp90 and Hsp70 facilitate protein folding but can also direct proteins for ubiquitin-mediated degradation. The mechanisms regulating these opposite activities involve Hsp binding to co-chaperones including CHIP and HOP at their C-termini. We demonstrated that the extreme C-termini of Hsp70 and Hsp90 contain phosphorylation sites targeted by kinases including CK1, CK2 and GSK3-β in vitro. The phosphorylation of Hsp90 and Hsp70 prevents binding to CHIP and thus enhances binding to HOP. Highly proliferative cells contain phosphorylated chaperones in complex with HOP and phospho-mimetic and non-phosphorylable Hsp mutant proteins show that phosphorylation is directly associated with increased proliferation rate. We also demonstrate that primary human cancers contain high levels of phosphorylated chaperones and show increased levels of HOP protein and mRNA. These data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-chaperone expression and chaperone modifications. In addition to identifying the pathway responsible for regulating chaperone-mediated protein folding/degradation balances in normal cells, the data provide novel mechanisms to account for the aberrant chaperone activities observed in human cancer cells and have implications for the application of anti-chaperone therapies in cancer treatment.
TL;DR: This work demonstrates that autophagy-inducing stress increases intracellular levels of acetylated inducible heat shock protein (hsp) 70, which binds to the Beclin-1–Vps34 complex, and highlights a regulatory mechanism of Vps34 activity, which involves acetylation hsp70 and KAP1-dependent SUMOylation of VPS34 bound to BeClin 1.
Abstract: Autophagy is a stress-induced catabolic process in which cytoplasmic components, sequestered in double-membrane autophagic vesicles (AVs) or autophagosomes, are delivered to lysosomes for degradation and recycling [Kroemer G, Marino G, Levine B (2010) Mol Cell 40(2):280–293]. Activity of the class III phosphatidylinositol-3-OH-kinase (PI3K) vacuolar protein-sorting (Vps) 34, bound to coiled-coil moesin-like B-cell lymphoma 2 (Bcl-2)–interacting protein Beclin-1, is required for phosphoinositide generation, essential for AV formation in autophagy [Cuervo AM (2010) Nat Cell Biol 12(8):735–737]. However, how autophagy-inducing stress regulates Vps34 activity has not been fully elucidated. Our findings demonstrate that autophagy-inducing stress increases intracellular levels of acetylated inducible heat shock protein (hsp) 70, which binds to the Beclin-1–Vps34 complex. Acetylated hsp70 also recruits E3 ligase for SUMOylation, KRAB–ZFP-associated protein 1 (KAP1), inducing Lys840 SUMOylation and increasing Vps34 activity bound to Beclin 1. Knockdown of hsp70 abolished the Beclin-1–Vps34 complex formation, as well as inhibited KAP1 binding to Vps34 and AV formation. Notably, autophagy-inducing stress due to histone deacetylase inhibitor treatment induced AV formation in the wild-type but not hsp70.1/3 knockout mouse embryonic fibroblasts MEFs. These findings highlight a regulatory mechanism of Vps34 activity, which involves acetylated hsp70 and KAP1-dependent SUMOylation of Vps34 bound to Beclin 1.
TL;DR: Curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.
TL;DR: It is proposed that pathological inclusions containing RNA‐binding proteins, such as TDP‐43 and FUS, might arise from SGs and discussed how SGs might contribute to neurodegeneration via toxic gain or loss‐of‐function mechanisms.
Abstract: Stress granules (SGs) are cytoplasmic foci that rapidly form when cells are exposed to stress. They transiently store mRNAs encoding house-keeping proteins and allow the selective translation of stress-response proteins (e.g. heat shock proteins). Besides mRNA, SGs contain RNA-binding proteins, such as T cell internal antigen-1 and poly(A)-binding protein 1, which can serve as characteristic SG marker proteins. Recently, some of these SG marker proteins were found to label pathological TAR DNA binding protein of 43 kDa (TDP-43)- or fused in sarcoma (FUS)-positive cytoplasmic inclusions in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In addition, protein aggregates in other neurodegenerative diseases (e.g. tau inclusions in Alzheimer's disease) show a co-localization with T cell internal antigen-1 as well. Moreover, several RNA-binding proteins that are commonly found in SGs have been genetically linked to neurodegeneration. This suggests that SGs might play an important role in the pathogenesis of these proteinopathies, either by acting as a seed for pathological inclusions, by mediating translational repression or by trapping essential RNA-binding proteins, or by a combination of these mechanisms. This minireview gives an overview of the general biology of SGs and highlights the recently identified connection of SGs with TDP-43, FUS and other proteins involved in neurodegenerative diseases. We propose that pathological inclusions containing RNA-binding proteins, such as TDP-43 and FUS, might arise from SGs and discuss how SGs might contribute to neurodegeneration via toxic gain or loss-of-function mechanisms.
TL;DR: The involvement of calmodulins and kinases in activation of heat shock factors has been implicated as an important event in governing high temperature tolerance.
TL;DR: This study provides a broad picture of differential accumulation of proteins and metabolites in postharvest citrus fruit, and gives new insights into HT improved fruit disease resistance during subsequent storage of ‘Kamei’ Satsuma mandarin.
Abstract: From field harvest to the consumer’s table, fresh citrus fruit spends a considerable amount of time in shipment and storage. During these processes, physiological disorders and pathological diseases are the main causes of fruit loss. Heat treatment (HT) has been widely used to maintain fruit quality during postharvest storage; however, limited molecular information related to this treatment is currently available at a systemic biological level. Mature ‘Kamei’ Satsuma mandarin (Citrus unshiu Marc.) fruits were selected for exploring the disease resistance mechanisms induced by HT during postharvest storage. Proteomic analyses based on two-dimensional gel electrophoresis (2-DE), and metabolomic research based on gas chromatography coupled to mass spectrometry (GC-MS), and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) were conducted. The results show resistance associated proteins were up-regulated in heat treated pericarp, such as beta-1, 3-glucanase, Class III chitinase, 17.7 kDa heat shock protein and low molecular weight heat-shock protein. Also, redox metabolism enzymes were down-regulated in heat treated pericarp, including isoflavone reductase, oxidoreductase and superoxide dismutase. Primary metabolic profiling revealed organic acids and amino acids were down-regulated in heat treated pericarp; but significant accumulation of metabolites, including tetradecanoic acid, oleic acid, ornithine, 2-keto-d-gluconic acid, succinic acid, turanose, sucrose, galactose, myo-inositol, glucose and fructose were detected. Noticeably, H2O2 content decreased, while, lignin content increased in heat treated pericarp compared to the control, which might increase fruit resistibility in response to external stress. Also, flavonoids, substances which are well-known to be effective in reducing external stress, were up-regulated in heat treated pericarp. This study provides a broad picture of differential accumulation of proteins and metabolites in postharvest citrus fruit, and gives new insights into HT improved fruit disease resistance during subsequent storage of ‘Kamei’ Satsuma mandarin. Interpretation of the data for the proteins and metabolites revealed reactive oxygen species (ROS) and lignin play important roles in heat treatment induced fruit resistance to pathogens and physiological disorders.
TL;DR: In this article, a Cauliflower mosaic virus 35S promoter was used to induce the heat shock factor (HSF) homologs in Arabidopsis (Arabidopsis thaliana) to activate the transcription of heat-induced genes, including HSFA2.
Abstract: There are 21 heat shock factor (HSF) homologs in Arabidopsis (Arabidopsis thaliana), of which members of class A1 (HSFA1a/HSFA1b/HSFA1d/HSFA1e) play the major role in activating the transcription of heat-induced genes, including HSFA2. Once induced, HSFA2 becomes the dominant HSF and is able to form heterooligomeric complexes with HSFA1. However, whether HSFA2 could function independently as a transcription regulator in the absence of the HSFA1s was undetermined. To address this question, we introduced a Cauliflower mosaic virus 35S promoter:HSFA2 construct into hsfa1a/hsfa1b/hsfa1d/hsfa1e quadruple knockout (QK) and wild-type (Wt) backgrounds to yield transgenic lines A2QK and A2Wt, respectively. Constitutive expression of HSFA2 rescued the developmental defects of the QK mutant and promoted callus formation in A2QK, but not in A2Wt, after heat treatment. Transcriptome analysis showed that heat stress response genes are differentially regulated by the HSFA1s and HSFA2; the genes involved in metabolism and redox homeostasis are preferentially regulated by HSFA2, while HSFA1-preferring genes are enriched in transcription function. Ectopic expression of HSFA2 complemented the defects of QK in tolerance to different heat stress regimes, and to hydrogen peroxide, but not to salt and osmotic stresses. Furthermore, we showed that HSFA1a/HSFA1b/HSFA1d are involved in thermotolerance to mild heat stress at temperatures as low as 27°C. We also noticed subfunctionalization of the four Arabidopsis A1-type HSFs in diverse abiotic stress responses. Overall, this study reveals the overlapping and distinct functions of class A1 and A2 HSFs and may enable more precise use of HSFs in engineering stress tolerance in the future.
TL;DR: The results suggest that HSP21 and pTAC5 are required for chloroplast development under heat stress by maintaining PEP function.
Abstract: Compared with small heat shock proteins (sHSPs) in other organisms, those in plants are the most abundant and diverse. However, the molecular mechanisms by which sHSPs are involved in cell protection remain unknown. Here, we characterized the role of HSP21, a plastid nucleoid-localized sHSP, in chloroplast development under heat stress. We show that an Arabidopsis thaliana knockout mutant of HSP21 had an ivory phenotype under heat stress. Quantitative real-time RT-PCR, run-on transcription, RNA gel blot, and polysome association analyses demonstrated that HSP21 is involved in plastid-encoded RNA polymerase (PEP)–dependent transcription. We found that the plastid nucleoid protein pTAC5 was an HSP21 target. pTAC5 has a C4-type zinc finger similar to that of Escherichia coli DnaJ and zinc-dependent disulfide isomerase activity. Reduction of pTAC5 expression by RNA interference led to similar phenotypic effects as observed in hsp21. HSP21 and pTAC5 formed a complex that was associated mainly with the PEP complex. HSP21 and pTAC5 were associated with the PEP complex not only during transcription initiation, but also during elongation and termination. Our results suggest that HSP21 and pTAC5 are required for chloroplast development under heat stress by maintaining PEP function.
TL;DR: It is shown that phosphorylation-induced destabilization of intersubunit interactions mediated by the N-terminal domain (NTD) results in the remodeling of the oligomer ensemble with an increase in smaller, activated species, predominantly 12-mers and 6-mers.
Abstract: The small heat shock protein αB-crystallin is an oligomeric molecular chaperone that binds aggregation-prone proteins. As a component of the proteostasis system, it is associated with cataract, neurodegenerative diseases, and myopathies. The structural determinants for the regulation of its chaperone function are still largely elusive. Combining different experimental approaches, we show that phosphorylation-induced destabilization of intersubunit interactions mediated by the N-terminal domain (NTD) results in the remodeling of the oligomer ensemble with an increase in smaller, activated species, predominantly 12-mers and 6-mers. Their 3D structures determined by cryo-electron microscopy and biochemical analyses reveal that the NTD in these species gains flexibility and solvent accessibility. These modulated properties are accompanied by an increase in chaperone activity in vivo and in vitro and a more efficient cooperation with the heat shock protein 70 system in client folding. Thus, the modulation of the structural flexibility of the NTD, as described here for phosphorylation, appears to regulate the chaperone activity of αB-crystallin rendering the NTD a conformational sensor for nonnative proteins.
TL;DR: Detailed understanding is provided of the Hsp70 protein family of rice, the crop species that is the major food for the world population, and promoter and transcript expression analysis divulges that HSp70 superfamily genes plays important role in heat stress.
Abstract: Heat stress results in misfolding and aggregation of cellular proteins. Heat shock proteins (Hsp) enable the cells to maintain proper folding of proteins, both in unstressed as well as stressed conditions. Hsp70 genes encode for a group of highly conserved chaperone proteins across the living systems encompassing bacteria, plants, and animals. In the cellular chaperone network, Hsp70 family proteins interconnect other chaperones and play a dominant role in various cell processes. To assess the functionality of rice Hsp70 genes, rice genome database was analyzed. Rice genome contains 32 Hsp70 genes. Rice Hsp70 superfamily genes are represented by 24 Hsp70 family and 8 Hsp110 family members. Promoter and transcript expression analysis divulges that Hsp70 superfamily genes plays important role in heat stress. Ssc1 (mitochondrial Hsp70 protein in yeast) deleted yeast show compromised growth at 37 °C. Three mitochondrial rice Hsp70 sequences (i.e., mtHsp70-1, mtHsp70-2, and mtHsp70-3) complemented the Ssc1 mutation of yeast to differential extents. The information presented in this study provides detailed understanding of the Hsp70 protein family of rice, the crop species that is the major food for the world population.
TL;DR: It is found for the first time that heat shock response controls autophagy thus connecting and coordinating the two extreme ends of the homeostatic systems in the eukaryotic cell.
TL;DR: It is reported that Heat Shock Protein 90 (Hsp90)-directed protein folding in mitochondria controls central metabolic networks in tumor cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis, and cellular redox status.
Abstract: Reprogramming of tumour cell metabolism contributes to disease progression and resistance to therapy, but how this process is regulated on the molecular level is unclear. Here we report that heat shock protein 90-directed protein folding in mitochondria controls central metabolic networks in tumour cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis and cellular redox status. Specifically, mitochondrial heat shock protein 90, but not cytosolic heat shock protein 90, binds and stabilizes the electron transport chain Complex II subunit succinate dehydrogenase-B, maintaining cellular respiration under low-nutrient conditions, and contributing to hypoxia-inducible factor-1α-mediated tumorigenesis in patients carrying succinate dehydrogenase-B mutations. Thus, heat shock protein 90-directed proteostasis in mitochondria regulates tumour cell metabolism, and may provide a tractable target for cancer therapy.
TL;DR: Current knowledge about the release and relevance of extracellular HSPs is addressed, including translocation across the plasma membrane and release associated with lipid vesicles, as well as the passive release after cell death by necrosis.
Abstract: The expression of heat shock proteins (HSPs) is a basic and well-conserved cellular response to an array of stresses. These proteins are involved in the repair of cellular damage induced by the stress, which is necessary for the salutary resolution from the insult. Moreover, they confer protection from subsequent insults, which has been coined stress tolerance. Because these proteins are expressed in subcellular compartments, it was thought that their function during stress conditions was circumscribed to the intracellular environment. However, it is now well established that HSPs can also be present outside cells where they appear to display a function different than the well-understood chaperone role. Extracellular HSPs act as alert stress signals priming other cells, particularly of the immune system, to avoid the propagation of the insult and favor resolution. Because the majority of HSPs do not possess a secretory peptide signal, they are likely to be exported by a nonclassic secretory pathway. Different mechanisms have been proposed to explain the export of HSPs, including translocation across the plasma membrane and release associated with lipid vesicles, as well as the passive release after cell death by necrosis. Extracellular HSPs appear in various flavors, including membrane-bound and membrane-free forms. All of these variants of extracellular HSPs suggest that their interactions with cells may be quite diverse, both in target cell types and the activation signaling pathways. This review addresses some of our current knowledge about the release and relevance of extracellular HSPs.
TL;DR: G protein–coupled receptor kinase 2 is identified as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal–regulated kinase regulation.
Abstract: Rationale:G protein–coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of β-adrenergic receptor kinase [bARKct]) is cardioprotective. Objective:The aim of this study was to elucidate the signaling mechanism that accounts for the prodeath signaling seen in the presence of elevated GRK2 and the cardioprotection afforded by the carboxyl-terminus of β-adrenergic receptor kinase. Methods and Results:Using in vivo mouse models of ischemic injury and also cultured myocytes, we found that GRK2 localizes to mitochondria, providing novel insight into GRK2-dependent pathophysiological signaling mechanisms. Mitochondrial localization of GRK2 in cardiomyocytes was enhanced after ischemic and oxidative stress, events...
TL;DR: Novel informations are presented on how the formation of HspB1/HspB5 complex can stimulate the activity of the oxidoresistance promoting enzyme glucose 6‐phosphate dehydrogenase through its interaction with newly formed highly phosphorylated HSpB1 homo‐oligomers.
TL;DR: It is proposed that Spm increases the HS response at transcriptional and translational levels and protects host plants from HS-induced damage.
Abstract: It is known that the polyamine (PA) biosynthetic pathway is modulated at the transcriptional level during abiotic stresses. Here we studied the expression of PA biosynthetic pathway genes upon exposure to heat shock (HS) in Arabidopsis and showed that the spermine (Spm) synthase gene (SPMS) and S-adenosylmethionine decarboxylase 2 gene are induced at the earliest stage, followed by the induction of the arginine decarboxylase 2 gene. Correspondingly, Spm content increased linearly upon HS, and putrescine (Put) and spermidine (Spd) content also increased but not thermospermine (T-Spm) content. Exogenously applied Spm had a potential to protect Arabidopsis plants from HS-induced damage. Such protection was also observed to the same extent with T-Spm and by Spd to a lesser extent but not by Put. Then we tested whether altered endogenous Spm content affects sensitivity to HS using both transgenic plants overexpressing SPMS and a Spm deficient (spms) mutant plant. The result revealed that the higher the Spm content the higher the thermotolerance. Even in the spms plant, representative genes encoding heat shock proteins (HSPs) and heat shock transcription factors were upregulated upon HS, while the expression of such genes was increased in a positively correlated manner with Spm content. Furthermore four kinds of HSPs (HSP101, HSP90, HSP70 and HSP17.6) were detected proportionally with the levels of their respective transcripts upon HS. We propose that Spm increases the HS response at transcriptional and translational levels and protects host plants from HS-induced damage.
TL;DR: This review aimed to summarize the experimental data concerning all aspects of the HS response in mammalian cells, such as HS-induced structural and functional alterations of cell membranes, the cytoskeleton and cellular organelles; the associated pathways that result in different modes of cell death and cell cycle arrest; and the effects of HS on transcription, splicing, translation, DNA repair, and replication.
Abstract: Heat shock (HS) is one of the best-studied exogenous cellular stresses. The cellular response to HS utilizes ancient molecular networks that are based primarily on the action of stress-induced heat shock proteins and HS factors. However, in one way or another, all cellular compartments and metabolic processes are involved in such a response. In this review, we aimed to summarize the experimental data concerning all aspects of the HS response in mammalian cells, such as HS-induced structural and functional alterations of cell membranes, the cytoskeleton and cellular organelles; the associated pathways that result in different modes of cell death and cell cycle arrest; and the effects of HS on transcription, splicing, translation, DNA repair, and replication.
TL;DR: In this paper, the authors developed a screen to identify Hsp90-defective mutants in E. coli and constructed homologous mutations in S. cerevisiae Hsp82 and identified several that caused defects in chaperone activity.
TL;DR: The regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage are discussed.
Abstract: O-linked N-acetyl-β-d-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (O-GlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced O-GlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer’s and Parkinson’s diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.