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1
Rehman, Saif ur, Asif Nadeem, Maryam Javed, Faiz-ul Hassan, Xier Luo, Ruqayya Bint Khalid, and Qingyou Liu. "Genomic Identification, Evolution and Sequence Analysis of the Heat-Shock Protein Gene Family in Buffalo." Genes 11, no. 11 (November 23, 2020): 1388. http://dx.doi.org/10.3390/genes11111388.
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Heat-shock proteins (HSP) are conserved chaperones crucial for protein degradation, maturation, and refolding. These adenosine triphosphate dependent chaperones were classified based on their molecular mass that ranges between 10–100 kDA, including; HSP10, HSP40, HSP70, HSP90, HSPB1, HSPD, and HSPH1 family. HSPs are essential for cellular responses and imperative for protein homeostasis and survival under stress conditions. This study performed a computational analysis of the HSP protein family to better understand these proteins at the molecular level. Physiochemical properties, multiple sequence alignment, and phylogenetic analysis were performed for 64 HSP genes in the Bubalus bubalis genome. Four genes were identified as belonging to the HSP90 family, 10 to HSP70, 39 to HSP40, 8 to HSPB, one for each HSPD, HSPH1, and HSP10, respectively. The aliphatic index was higher for HSP90 and HSP70 as compared to the HSP40 family, indicating their greater thermostability. Grand Average of hydropathicity Index values indicated the hydrophilic nature of HSP90, HSP70, and HSP40. Multiple sequence alignment indicated the presence of highly conserved consensus sequences that are plausibly significant for the preservation of structural integrity of proteins. In addition, this study has expanded our current knowledge concerning the genetic diversity and phylogenetic relatedness of HSPs of buffalo with other mammalian species. The phylogenetic tree revealed that buffalo is more closely related to Capra hircus and distantly associated with Danio rerio. Our findings provide an understanding of HSPs in buffalo at the molecular level for the first time. This study highlights functionally important HSPs and indicates the need for further investigations to better understand the role and mechanism of HSPs.
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Ajayi, Oyeyemi O., Sunday O. Peters, Marcos De Donato, Sunday O. Sowande, Fidalis D. N. Mujibi, Olanrewaju B. Morenikeji, Bolaji N. Thomas, Matthew A. Adeleke, and Ikhide G. Imumorin. "Computational genome-wide identification of heat shock protein genes in the bovine genome." F1000Research 7 (September 20, 2018): 1504. http://dx.doi.org/10.12688/f1000research.16058.1.
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Background: Heat shock proteins (HSPs) are molecular chaperones known to bind and sequester client proteins under stress. Methods: To identify and better understand some of these proteins, we carried out a computational genome-wide survey of the bovine genome. For this, HSP sequences from each subfamily (sHSP, HSP40, HSP70 and HSP90) were used to search the Pfam (Protein family) database, for identifying exact HSP domain sequences based on the hidden Markov model. ProtParam tool was used to compute potential physico-chemical parameters detectable from a protein sequence. Evolutionary trace (ET) method was used to extract evolutionarily functional residues of a homologous protein family. Results: We computationally identified 67 genes made up of 10, 43, 10 and 4 genes belonging to small HSP, HSP40, HSP70 and HSP90 families respectively. These genes were widely dispersed across the bovine genome, except in chromosomes 24, 26 and 27, which lack bovine HSP genes. We found an uncharacterized outer dense fiber (ODF1) gene in cattle with an intact alpha crystallin domain, like other small HSPs. Physico-chemical characteristic of aliphatic index was higher in HSP70 and HSP90 gene families, compared to small HSP and HSP40. Grand average hydropathy showed that small HSP (sHSP), HSP40, HSP70 and HSP90 genes had negative values except for DNAJC22, a member of HSP40 gene family. The uniqueness of DNAJA3 and DNAJB13 among HSP40 members, based on multiple sequence alignment, evolutionary trace analysis and sequence identity dendrograms, suggests evolutionary distinct structural and functional features, with unique roles in substrate recognition and chaperone functions. The monophyletic pattern of the sequence identity dendrograms of cattle, human and mouse HSP sequences suggests functional similarities. Conclusions: Our computational results demonstrate the first-pass in-silico identification of heat shock proteins and calls for further investigation to better understand their functional roles and mechanisms in Bovidae.
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Matsuoka, Erina, Naoki Kato, and Masakazu Hara. "Induction of the heat shock response in Arabidopsis by heat shock protein 70 inhibitor VER-155008." Functional Plant Biology 46, no. 10 (2019): 925. http://dx.doi.org/10.1071/fp18259.
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The heat shock protein 90 (HSP90) inhibitor, geldanamycin, is a chemical inducer of the heat shock response (HSR) in Arabidopsis. Geldanamycin is thought to activate the heat shock signal by dissociating the HSP90-heat shock factor (HSF) complex. Recent studies have indicated that plant HSP70 is also associated with HSF, suggesting that inhibition of HSP70 may induce the HSR. However, no studies have been conducted to test this hypothesis. Here, we found that a specific HSP70 inhibitor VER-155008 activated the promoter of a small HSP gene (At1 g53540, HSP17.6C-CI) of Arabidopsis, which was shown to be activated by geldanamycin and other HSP90 inhibitors. The production of HSP17.6C-CI, HSP70 and HSP90.1 proteins in Arabidopsis was enhanced by the addition of VER-155008. The reduction of chlorophyll contents by heat shock was ameliorated by VER-155008. Chaperone analyses indicated that VER-155008 inhibited the chaperone activities of wheat germ extract and human HSP70/HSP40, respectively. These results suggest that the inhibition of HSP70 by VER-155008 enhanced the heat tolerance of Arabidopsis by inducing the HSR in the plant.
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Ali, Adnan, and John J. Heikkila. "Enhanced accumulation of constitutive heat shock protein mRNA is an initial response of eye tissue to mild hyperthermia in vivo in adult Xenopus laevis." Canadian Journal of Physiology and Pharmacology 80, no. 11 (November 1, 2002): 1119–23. http://dx.doi.org/10.1139/y02-133.
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We have examined the effect of mild hyperthermia in vivo on heat shock transcription factor (HSF) binding activity and heat shock protein (hsp) gene expression in eye tissue of adult Xenopus laevis. A specific interaction between HSF and a synthetic oligonucleotide corresponding to the proximal heat shock element of the Xenopus hsp70B gene was greatly enhanced in eyes from hyperthermic animals compared with controls. Given these results, we examined the effect of hyperthermia in vivo on the expression of five hsp genes (hsp70, hsc70, BiP, hsp90, and hsp30) in eye tissue. Interestingly, at 28°C constitutively expressed hsp genes hsc70, BiP, and hsp90 were strongly enhanced, with further accumulation at 30°C. However, hsp70 and hsp30 mRNA accumulation were not detectable at 28°C but were strongly induced at 30°C. No enhancement of the relative levels of cytoskeletal actin mRNA was observed in the eye tissue of hyperthermic animals. These results suggest that one of the primary responses of eye tissue to hyperthermia in vivo is in the elevation of mRNAs encoding a set of constitutively expressed molecular chaperones.Key words: Xenopus, mRNA, eye, heat shock, heat shock factor.
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STEPHANOU, A., V. AMIN, D. A. ISENBERG, S. AKIRA, T. KISHIMOTO, and David S. LATCHMAN. "Interleukin 6 activates heat-shock protein 90β gene expression." Biochemical Journal 321, no. 1 (January 1, 1997): 103–6. http://dx.doi.org/10.1042/bj3210103.
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The levels of the cytokine interleukin-6 (IL-6) and the heat-shock protein hsp90 have both been reported to be elevated in patients with active systemic lupus erythematosus (SLE). We show that hsp90 protein accumulates to increased levels in both HuH7 hepatoma cells and peripheral blood mononuclear cells (PBMCs) treated with IL-6. In PBMCs this effect occurs without induction of the other hsps, paralleling the specific elevation of hsp90 in SLE. IL-6 is able to activate the hsp90 gene promoter directly; this activation can also be achieved by overexpressing either of the transcription factors NF-IL-6 or NF-IL-6β whose synthesis is induced by IL-6 treatment. Hence the induction of hsp90 protein accumulation by IL-6 is likely to be dependent on the enhanced activity of the hsp90β gene promoter produced by increased levels of NF-IL-6 and/or NF-IL-6β. These effects are discussed in terms of the role of hsp90 in the normal immune system and the mechanism of its activation in patients with SLE.
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Birbo, Bereket, Elechi E. Madu, Chikezie O. Madu, Aayush Jain, and Yi Lu. "Role of HSP90 in Cancer." International Journal of Molecular Sciences 22, no. 19 (September 25, 2021): 10317. http://dx.doi.org/10.3390/ijms221910317.
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HSP90 is a vital chaperone protein conserved across all organisms. As a chaperone protein, it correctly folds client proteins. Structurally, this protein is a dimer with monomer subunits that consist of three main conserved domains known as the N-terminal domain, middle domain, and the C-terminal domain. Multiple isoforms of HSP90 exist, and these isoforms share high homology. These isoforms are present both within the cell and outside the cell. Isoforms HSP90α and HSP90β are present in the cytoplasm; TRAP1 is present in the mitochondria; and GRP94 is present in the endoplasmic reticulum and is likely secreted due to post-translational modifications (PTM). HSP90 is also secreted into an extracellular environment via an exosome pathway that differs from the classic secretion pathway. Various co-chaperones are necessary for HSP90 to function. Elevated levels of HSP90 have been observed in patients with cancer. Despite this observation, the possible role of HSP90 in cancer was overlooked because the chaperone was also present in extreme amounts in normal cells and was vital to normal cell function, as observed when the drastic adverse effects resulting from gene knockout inhibited the production of this protein. Differences between normal HSP90 and HSP90 of the tumor phenotype have been better understood and have aided in making the chaperone protein a target for cancer drugs. One difference is in the conformation: HSP90 of the tumor phenotype is more susceptible to inhibitors. Since overexpression of HSP90 is a factor in tumorigenesis, HSP90 inhibitors have been studied to combat the adverse effects of HSP90 overexpression. Monotherapies using HSP90 inhibitors have shown some success; however, combination therapies have shown better results and are thus being studied for a more effective cancer treatment.
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Le Thi, Man, Na Nguyen Quoc, Huyen Tran Thi Thanh, Hong La Viet, and Bang Cao Phi. "Identification and analysis of HSP90 genes in papaya (Carica papaya L.) by using bioinformatics method." Journal of Science Natural Science 66, no. 4F (November 2021): 196–204. http://dx.doi.org/10.18173/2354-1059.2021-0083.
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The HSP90 gene family has been shown to play an important role in the tolerance and development of plants. Papaya, which is a fruit crop with high nutritional value, is native to the tropics but now is widely cultivated in many subtropical regions of the world. Therefore, papaya plants have to face many environmental factors during their life. This study aims to identify and analyze the HSP90 gene family in papaya by bioinformatics method. A total of seven HSP90 genes have been identified in the genome of papaya (Carica papaya L.) by using the bioinformatic methods. The full-length genomic sequence of papaya HSP90 genes were ranging from 2650 to 8136 nucleotides, non continuous coding, with number of intro ranging from two to 19. The predicted protein sequences included from 348 to 796 amino acids, according to the molecular weight ranged from 39.92 to 90.61 kDa. Among seven CpHSP90, the two CpHSP90-1 and CpHSP90-4 were considered pseudogenes due to their small size. These proteins were acidic with a pI value ranging from 4.69 to 5.42, except CpHSP90-1 (pI 7.03). Based on the protein structure, subcellular localization and the phylogenic analysis, the papaya HSP90 were divided into two groups, I (cytoplasmic HSP90, four members) and II (organelle HSP90, three members). Analysis of transcriptomes showed that the papaya HSP90s were differentially expressed in different tissues at different development stages. In which, most of the papaya HSP90 is highly expressed in flower buds or in fruits at stage 2 or stage 3. CpHSP90-2 had the highest level of expression, followed by CpHSP90-5. In contrast, CpHSP90-1 was not expressed or very weakly expressed in these studied tissues. All of seven HSP90 genes of papaya were induced by freeze-thaw awakening treatment (in comparison with control treatment), among them, CpHSP90-1 was strongest induced by stress (12.13-folds), however, it was a pseudogene and had a very low level of basal expression. CpHSP90-2 had a high induction level (2.81- folds), and also had a high basal expression level compared to other HSP90 genes of papaya. The results of this work have an important significance and will serve as a base for the further research on gene cloning, functional analysis of HSP90 genes and breeding of papaya in response to environmental abiotic stresses and the development of this fruit crop.
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Gupta, Payal, Amit K. Mittal, Dennis D. Weisenburger, Philip Bierman, and Shantaram S. Joshi. "Heat-Shock Protein Signature Is Associated with Refractory Chronic Lymphocytic Leukemia Cells From Different In Vivo Microenvironments,." Blood 118, no. 21 (November 18, 2011): 3866. http://dx.doi.org/10.1182/blood.v118.21.3866.3866.
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Abstract Abstract 3866 Chronic Lymphocytic Leukemia (CLL) is a monoclonal B-cell disorder with accumulation of leukemic cells in peripheral blood, bone marrow and lymphoid organs. It presents with a heterogeneous clinical course. Many patients survive long periods of time without any need for treatment, whereas other patients show resistance to treatment or relapse soon after administration of therapy. Although some prognostic markers such as mutational status of immunoglobulin variable heavy chain, chromosomal abnormalities, CD38 levels, or ZAP-70 expression may help predict at initial diagnosis which patients will have more aggressive disease, the exact factors that can determine chances of remission in CLL are still not clear, making treatment challenging. Furthermore, CLL remains an incurable disease, necessitating a way for controlling its progression. Identifying novel molecular signatures associated with refractory CLL disease may help devise targeted treatment strategies and thus may prolong survival times and prevent the progression of CLL in relapsed patients. Considering this, we performed gene expression profiling (GEP) on peripheral blood (PB), bone marrow (BM) and lymph node (LN) samples collected at the time of diagnosis. We divided CLL samples into 3 groups based on their response to treatment; i) Stable CLL group: asymptomatic patients requiring no treatment, ii) Treated but stable CLL group: patients required treatment but had stable disease for at least one year after the end of the treatment cycle, and iii) Relapsed CLL: patients who relapsed within a year of end of the treatment cycle. Significance analysis of microarray (SAM) revealed that the heat-shock protein (HSP) signature (HSJ2, HSP70, HSP90, HSP60, HSP10, HSP 105, HSP40, HSP27, HSPA2, HSJ1, HSF4, HSPCA), BCR signaling pathway (JUN, NFATC4, NFKBIE, PPP3CB, TRAF3, CD81, CCT4), activation markers (CD81, CD83) and MMPs (MMP3, MMP9) were overexpressed in relapsed PB-CLL (n=3) compared to stable PB-CLL (n=6) and treated but stable PB-CLL (n=10). Overexpression of heat-shock protein signature genes were further observed in additional relapsed PB-CLL (n=6) group compared to other two PB-CLL (n=22) group. Interestingly, the HSP signature was consistently overexpressed in relapsed BM-CLL (n=6) and LN-CLL (n=12) compared to stable and treated but stable BM-CLL (n=11) and LN-CLL (n=3) groups. HSPs are considered chaperones of tumorigenesis and known to enhance survival, migration, and proliferation of tumor cells which may contribute to relapse in patients. Furthermore, the HSPs genes (HSP90 and HSP70) were significantly overexpressed in LN-CLL as compared to PB-CLL which implies important role of the microenviroment in rendering CLL refractory. To investigate the link between the expression of the individual genes with the aggressiveness of the disease, Kaplan-Meier log-rank tests were performed. We found that the higher expression of HSP90A, HSP90B, HSJ, and MMP9 were significantly (p<0.05) associated with shorter time to treatment. In summary, our study suggests that HSP genes are overexpressed in refractory CLL patients and thus are promising targets to improve clinical outcome. Disclosures: No relevant conflicts of interest to declare.
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Fu, Ssu-Ju, Meng-Chun Hu, Cheng-Tsung Hsiao, An-Ting Cheng, Tsung-Yu Chen, Chung-Jiuan Jeng, and Chih-Yung Tang. "Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect." International Journal of Molecular Sciences 22, no. 11 (May 30, 2021): 5859. http://dx.doi.org/10.3390/ijms22115859.
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The ClC-2 channel plays a critical role in maintaining ion homeostasis in the brain and the testis. Loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the white matter disease leukodystrophy. Clcn2-deficient mice display neuronal myelin vacuolation and testicular degeneration. Leukodystrophy-causing ClC-2 mutant channels are associated with anomalous proteostasis manifesting enhanced endoplasmic reticulum (ER)-associated degradation. The molecular nature of the ER quality control system for ClC-2 protein remains elusive. In mouse testicular tissues and Leydig cells, we demonstrated that endogenous ClC-2 co-existed in the same protein complex with the molecular chaperones heat shock protein 90β (Hsp90β) and heat shock cognate protein (Hsc70), as well as the associated co-chaperones Hsp70/Hsp90 organizing protein (HOP), activator of Hsp90 ATPase homolog 1 (Aha1), and FK506-binding protein 8 (FKBP8). Further biochemical analyses revealed that the Hsp90β-Hsc70 chaperone/co-chaperone system promoted mouse and human ClC-2 protein biogenesis. FKBP8 additionally facilitated membrane trafficking of ClC-2 channels. Interestingly, treatment with the Hsp90-targeting small molecule 17-allylamino-17-demethoxygeldanamycin (17-AAG) substantially boosted ClC-2 protein expression. Also, 17-AAG effectively increased both total and cell surface protein levels of leukodystrophy-causing loss-of-function ClC-2 mutant channels. Our findings highlight the therapeutic potential of 17-AAG in correcting anomalous ClC-2 proteostasis associated with leukodystrophy.
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Shyamala, G., Y. Gauthier, S. K. Moore, M. G. Catelli, and S. J. Ullrich. "Estrogenic regulation of murine uterine 90-kilodalton heat shock protein gene expression." Molecular and Cellular Biology 9, no. 8 (August 1989): 3567–70. http://dx.doi.org/10.1128/mcb.9.8.3567-3570.1989.
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Murine uterine steady-state protein levels of the 90-kilodalton heat shock protein (HSP90) have been demonstrated recently to be increased by estrogen in a target tissue- and steroid-specific manner (C. Ramachandran, M.G. Catelli, W. Schneider, and G. Shyamala, Endocrinology 123:956-961, 1988). We now report that this regulation occurred with both the HSP86 and HSP84 forms of HSP90 as well as with the 94-kilodalton glucose-regulated protein. At the mRNA level, this response was greatest for HSP86 (15-fold). In contrast, estradiol had no significant effect on HSP70.
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Shyamala, G., Y. Gauthier, S. K. Moore, M. G. Catelli, and S. J. Ullrich. "Estrogenic regulation of murine uterine 90-kilodalton heat shock protein gene expression." Molecular and Cellular Biology 9, no. 8 (August 1989): 3567–70. http://dx.doi.org/10.1128/mcb.9.8.3567.
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Murine uterine steady-state protein levels of the 90-kilodalton heat shock protein (HSP90) have been demonstrated recently to be increased by estrogen in a target tissue- and steroid-specific manner (C. Ramachandran, M.G. Catelli, W. Schneider, and G. Shyamala, Endocrinology 123:956-961, 1988). We now report that this regulation occurred with both the HSP86 and HSP84 forms of HSP90 as well as with the 94-kilodalton glucose-regulated protein. At the mRNA level, this response was greatest for HSP86 (15-fold). In contrast, estradiol had no significant effect on HSP70.
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Mandrioli, M., E. Zanetti, A. Nardelli, and G. C. Manicardi. "Potential role of the heat shock protein 90 (hsp90) in buffering mutations to favour cyclical parthenogenesis in the peach potato aphid Myzus persicae (Aphididae, Hemiptera)." Bulletin of Entomological Research 109, no. 4 (September 12, 2018): 426–34. http://dx.doi.org/10.1017/s0007485318000688.
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AbstractHeat-shock proteins 90 (hsp90s) are a class of molecules able to stabilize a network of ‘client’ proteins that are involved in several processes. Furthermore, recent studies indicated that mutations in the hsp90-encoding gene induce a wide range of phenotypic abnormalities, which have been interpreted as an increased sensitivity of different developmental pathways to hidden/cryptic mutations. In order to verify the role of hsp90 in aphids, we amplified and sequenced the hsp90 gene in 17 lineages of the peach potato aphid Myzus persicae (Sulzer, 1776) looking for the presence of mutations. In particular, we compared lineages with different reproductive modes (obligate vs. cyclical parthenogenesis), propensity to develop winged females and karyotype stability. Differently from the cyclical parthenogenetic lineages that possessed functional hsp90 genes, the seven analysed asexual lineages showed severe mutations (including frameshift and non-sense mutations). In vivo functional assays with the hsp90-inhibitor geldanamycin showed that some lineages with cyclical parthenogenesis may lose their ability to induce sexuales in the absence of active hsp90 revealing the presence of cryptic mutations in their genomes. As a whole, our data suggest that hsp90 could play in aphids a role in buffering hidden/cryptic mutations that disrupt cyclical parthenogenesis.
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STEPHANOU, Anastasis, A. David ISENBERG, Shizuo AKIRA, Tadamitsu KISHIMOTO, and S. David LATCHMAN. "The nuclear factor interleukin-6 (NF-IL6) and signal transducer and activator of transcription-3 (STAT-3) signalling pathways co-operate to mediate the activation of the hsp90β gene by interleukin-6 but have opposite effects on its inducibility by heat shock." Biochemical Journal 330, no. 1 (February 15, 1998): 189–95. http://dx.doi.org/10.1042/bj3300189.
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The levels of the 90 kDa heat-shock protein (hsp90) and the activity of the hsp90β gene promoter are increased in response to treatment by interleukin (IL)-6. The hsp90β gene promoter contains binding sites for the transcription factors nuclear factor IL-6 (NF-IL6) and signal transducer and activator of transcription 3 (STAT-3), which are activated respectively by the mitogen-activated-protein-kinase and Jak-kinase pathways following IL-6 treatment. Both these factors can activate the hsp90 promoter and have a strong synergistic effect on its activity, which appears to be critical for IL-6-mediated activation of the promoter. Interestingly, the two factors interact differently with the heat-shock factor (HSF) and a heat-shock stress. Thus STAT-3 reduces the stimulatory effect of heat shock whereas NF-IL6 enhances it. When applied together, heat shock and IL-6 produce only weak activation of the hsp90 promoter compared with either stimulus alone, indicating that the inhibitory effect of STAT-3 on HSF predominates under these conditions. In contrast, IL-1, which activates only the NF-IL6 pathway, synergizes with heat shock to produce strong activation of hsp90. These effects are discussed in terms of the multiple stimuli that may regulate the hsp90 promoter in unstressed cells and their interaction with its stress-mediated activation.
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Jolly, Emmitt R. "HSP70, HSP90A, and HSP90B are Differentially Regulated in Response to Thermal, Osmotic and Hypoxic Stressors." Annals of Experimental and Molecular Biology 1, no. 1 (2018): 1–9. http://dx.doi.org/10.23880/aemb-16000101.
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The Heat shock proteins, Hsp70 and Hsp90 are highly conserved and play a significant role in cellular response to a variety of stressors. In response to stressors, cellular expression levels of these heat shock proteins are increased to stabilize degrading proteins and to initiate thermotolerance among other complex functions. Maintenance of physiological temperature in all organisms is imperative to ensure that biological systems function normally. This is especially critical for cold-blooded organisms whose internal temperature is subject to their environmental conditions. High temperatures and other stressors can deleteriously affect animal motility, its ability to avoid predators, neuronal activity and affect neuropeptide populations. However, the effect of stressors on muscle and on neuronal activity are not always equal. Here we use the important commercially important Jonah crab, Cancer borealis as a model to assess the effect of different stressors on transcript levels of the major heat shock proteins, HSP70, HSP90A and HSP90B. Since these genes have not been identified or sequenced in C borealis, we cloned each gene and we demonstrate that a) these genes have different expression profiles in thermal, osmotic and hypoxic stresses and that b) these genes are differentially expressed in muscle and brain cells.
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Kozhabek, Zh, J. L. Үu, and X. L. Wang. "Analysis of the HSP17.6 protein mechanism in BBSV infection." BULLETIN of the L.N. Gumilyov Eurasian National University. BIOSCIENCE Series 135, no. 2 (2021): 38–47. http://dx.doi.org/10.32523/2616-7034-2021-135-2-38-47.
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Beet black scorch virus (BBSV) has been reported as a natural pathogen of sugar beet and distributed all over the world, causing great economic losses to the sugar industry. Research on interactions between BBSV and its host by using model plant Nicotiana benthamiana is significantly important and nessesary for understanding virus infection process and exploring plant resistance mechanism. The results of sequencing the transcriptome of N. benthamiana infected with BBSV as well as gene screening in response to viral infection revealed upregulation of the small heat shock protein 17.6 gene (NbHSP17.6) and the effect of the protein on resistance to the virus. To further examine the involvement of HSP17.6 in defense responses in N. benthamiana, we tested interaction between HSP17.6 and other heat shock proteins such as HSP70 and HSP90 as well as BBSV encoded proteins. The results showed that HSP17.6 interacted with HSP70 and HSP90 but not with BBSV encoded proteins. When combined with other available results, it is possible that HSP17.6 acted as a small molecular chaperone to facilitate proper refolding of the specific proteins HSP70 and HSP90 required for BBSV infection and/or replication.
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Heimberger, Tanja, Mindaugas Andrulis, Stephanie Fischbach, Thorsten Stühmer, Hermann Einsele, Ralf C. Bargou, and Manik Chatterjee. "Inhibition of the Heat Shock Transcription Factor 1 as a Potential New Therapeutic Strategy to Target Multiple Oncogenic Heat Shock Proteins in Multiple Myeloma." Blood 114, no. 22 (November 20, 2009): 2829. http://dx.doi.org/10.1182/blood.v114.22.2829.2829.
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Abstract Abstract 2829 Poster Board II-805 Introduction: We could recently show that the heat shock proteins (HSP) HSP90 and HSP70 are frequently overexpressed in multiple myeloma (MM), stabilize as molecular chaperones various oncogenic proteins and contribute to survival of MM cells. Currently, several clinical Phase I/II studies are under way to evaluate the concept of pharmacological HSP90 blockade in human cancer. Under cellular stress conditions the heat shock transcription factor 1 (HSF1) has a key regulatory role for the up-regulation of HSP. Importantly, it has been observed that treatment with the proteasome inhibitor bortezomib, a clinically effective anti-MM agent, induces up-regulation of HSP90, HSP70 and HSP27. Furthermore, it has recently been demonstrated that HSF1 can protect cells from oncogene-driven malignant transformation. We therefore analyzed the role of HSF1 for the malignant growth of MM cells. Methods: Western analyses were performed to determine HSF1 expression and regulation in different human MM cell lines. To examine the expression of HSF1 and different HSP like HSP90, HSP70 and HSP27 in situ, samples from 60 bone marrow biopsies obtained from MM patients were immunohistochemically stained. To analyze the role of HSF1 for the survival of MM cells, HSF1 was either selectively depleted by siRNA-mediated knockdown using a pSUPER-based siRNA expression vector or targeted by treatment with a novel pharmacological HSF1 inhibitor triptolide. In addition, pharmacological inhibition of HSF1 was combined with concomitant pharmacological inhibition of either HSP90 (with the novel inhibitor NVP-AUY922) or bortezomib. Furthermore, gene expression analyses with an Affymetrix GeneChip were performed to identify HSF1 target genes in MM cells. Results: Here, we show that HSF1 is frequently overexpressed in MM cell lines in vitro and in the majority of the analyzed MM biopsies in situ, but not in MGUS or in normal plasma cells. Blockade of HSF1 either by siRNA-mediated knockdown or treatment with the novel pharamacological HSF1 inhibitor triptolide led to a strong induction of apoptosis in cells of the MM cell lines INA-6 and MM.1s. Importantly, also primary MM cells showed apoptosis induction after triptolide treatment. HSF1 inhibition led to downregulation of HSP70, HSP27 and HSP90. Gene expression analysis revealed a number of additional molecular targets of HSF1 involved in apoptosis regulation. Furthermore, initial experiments indicated that the apoptotic effect of pharmacological HSF1 inhibition is enhanced by the concomitant pharmacological inhibition of either HSP90 or the proteasome. Conclusion: We demonstrate that HSF1 is overexpressed in MM, contributes to the survival of MM cells and controls the activity of oncogenic HSP like HSP90, HSP70 and HSP27. Targeting HSF1 may therefore represent an attractive potential therapeutic strategy in MM, in particular in combination with HSP90 or proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Walsby, Elisabeth J., Amanda F. Gilkes, Valerie Walsh, Kenneth I. Mills, and Alan K. Burnett. "Hsp90 Expression in Acute Myeloid Leukaemia." Blood 104, no. 11 (November 16, 2004): 4471. http://dx.doi.org/10.1182/blood.v104.11.4471.4471.
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Abstract Heat shock protein inhibitors are a potential new class of anti-leukaemic agents with FLT-3 inhibitory activity. 17-allylamino-17-demethoxygeldanamycin (17-AAG) targets Hsp90 which functions as a molecular chaperone protein that promotes folding of nascent and stress denatured proteins helping them to achieve the correct conformation or targeting them for degradation. Hsp90 conformation is altered by binding ATP to a hydrophobic N-terminal pocket leading to hydrolysis which allows the protein to interact with a co-chaperone complex. 17-AAG fills the ATP binding pocket, displacing the nucleotide and inhibiting the function of Hsp90 as a chaperone. 17-AAG may affect signal transduction resulting from client proteins such as p53, c-Raf-1, Akt, Bcr-Abl and FLT-3. The level of expression of Hsp90 in AML is unknown. To examine the expression 252 AML cases and 9 normal samples were assessed by U133A GeneChips with the data analysed by MAS5 and GeneSpring 6.2.1 to give normalised gene expression of Hsp90α and β, a subset of which were then validated by real-time quantitative RT-PCR. The normalised expression range of Hspα was 0.132 to 2.727 with a mean of 0.982 (n=252) which was not significantly different from normal (0.876: n=9). Hsp90α expression was not significantly different in FAB groups, cytogenetic risk group, FLT-3 status overall or within cytogenetic risk groups. The expression of Hsp90β in the AML samples (n=252) (0.959: range 0.171 to 3.397) was not different from normal samples (0.944: range 0.535 to 1.095). However the APL subgroup (M3) (n=31) had a lower expression (0.722) than the other FAB groups (M0, M1, M2, M4, M5, M6, M7) p=0.029. There was no difference within other FAB subgroups. Apart from the influence of the t(15;17) subgroup expression levels did not vary significantly in the cytogenetic risk groups, or with the presence of a FLT-3 mutation overall or within cytogenetic risk groups. Conclusion: Hsp90 isoform expression in AML is variable over a 21 fold range. Expression does not correlate with FAB, cytogenetic risk group or FLT-3 mutation status. The relationship to clinical outcome is currently being analysed.
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Girvitz, T. L., P. M. Ouimet, and M. Kapoor. "Heat shock protein 80 ofNeurospora crassa: Sequence analysis of the gene and expression during the asexual phase." Canadian Journal of Microbiology 46, no. 11 (November 1, 2000): 981–91. http://dx.doi.org/10.1139/w00-095.
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Heat shock protein 80 (Hsp80) of Neurospora crassa, a member of the stress-90 protein family, is a cytosolic molecular chaperone that interacts directly with Hsp70 to form a hetero-oligomeric complex. The complete nucleotide sequence of the gene encoding this protein, along with the 5'- and 3'-flanking DNA, is reported. The coding sequence is interrupted by two introns, 61 and 30 nucleotides, respectively, in length. The deduced amino acid sequence corresponds to a 695-residue polypeptide with a calculated molecular mass of 78 894 Da and an average pI of 4.94. Primer extension experiments demonstrated two transcription start sites, a major and a minor one. No sequence motifs resembling the standard eukaryotic heat shock elements were evident in the putative promoter region. Immunoblot analysis showed Hsp80 protein to be present in the mature, dormant conidia, while the hsp80 transcripts were not detected. Both the transcripts and the protein were present in the germinating conidia in the absence of externally applied stress.Key words: Hsp90, filamentous fungi, sequence, conidia, germination.
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Younis, Fawzy. "Expression pattern of heat shock protein genes in sheep." Mansoura Veterinary Medical Journal 21, no. 1 (March 25, 2020): 1–5. http://dx.doi.org/10.35943/mvmj.2020.21.001.
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Objective: To recognize the expression patterns of HSP 70 and HSP 90 genes of two local sheep breeds. Design: Descriptive study Animals: Fifty ewes (25 Barki and 25 Abu Dlik). Procedures: This investigation was carried out on fifty sheep at the northwest coast and southeast of triangle Halayeb and Shalateen during the months of March and May 2018 and 2019 (average day time temperatures: 25–35 ◦C; relative humidity: 55–65%). Total RNA was extracted using easy-RED™ Total RNA Extraction Kit. The primers for qPCR were designed on the basis of prior sequence information available at National Center for Biotechnology Information (NCBI) for with the target HSP70 and 90 genes. The Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) gene, housekeeping gene, was used for normalization qPCR data. The desired genes were amplified for relative expression measurements. Tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1 β, IL-6, IL-10, IL-12) were assayed. Results: The expression levels of the HSP70 and HSP90 genes and the genes in Abu Dlik sheep were observed to relatively up-regulated than those in Barki sheep. Abu Dlik breed exhibited an up-regulate mRNA level of Hsp70 and Hsp90 genes (1.70440938 vs 1.362954) while the Barki breed showed a down-regulated pattern (0.8550442 vs 0.4289764). In Abu Dlik ewes HSP70 gene exhibited a higher mRNA level than HSP90 mRNA. Conclusion and clinical relevance: Gene expression patterns of HSP 70 and HSP 90, as well as cytokines modulations, can be used as a biological marker and a reference point in animals to identify, manipulate and cross-breed for improving the genetic potential and adaptability in sheep which tolerates the harsh environmental conditions, especially the heat stress., and it is necessary to manage stress at a cellular level.
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Kim, Won-Seok, Kiyun Park, Jae-Won Park, Sun-Ho Lee, Ji-Hoon Kim, Yong-Jun Kim, Gun-Hee Oh, et al. "Transcriptional Responses of Stress-Related Genes in Pale Chub (Zacco platypus) Inhabiting Different Aquatic Environments: Application for Biomonitoring Aquatic Ecosystems." International Journal of Environmental Research and Public Health 19, no. 18 (September 12, 2022): 11471. http://dx.doi.org/10.3390/ijerph191811471.
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Pale chub (Zacco platypus) is a dominant species in urban rivers and reservoirs, and it is used as an indicator to monitor the effects of environmental contaminants. Gene responses at the molecular level can reflect the health of fish challenged with environmental stressors. The objective of this study was to identify correlations between water quality factors and the expression of stress-related genes in Z. platypus from different lake environments (Singal and Juam Lakes). To do so, transcriptional responses of genes involving cellular homeostasis (heat-shock protein 70, HSP70; heat-shock protein 90, HSP90), metal detoxification (metallothionein, MT), and antioxidation (superoxide dismutase, SOD; catalase, CAT) were analyzed in the gill and liver tissues of Z. platypus. HSP70, HSP90, and MT genes were overall upregulated in Z. platypus from Singal Lake, which suffered from poorer water quality than Juam Lake. In addition, gene responses were significantly higher in Singal Lake outflow. Upregulation of HSP70, HSP90, and MT was significantly higher in Z. platypus gills than in the liver tissue. In addition, integrated biomarker response and heatmap analysis determined correlations between expression of biomarker genes or water quality factors and sampling sites of both lakes. These results suggest that stress-related genes used as multiple biomarkers may reflect spatial characteristics and water quality of different lake environments, and they can be used for biomonitoring and ecological risk assessment.
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Krone, Patrick H., Zsolt Lele, and Jennifer B. Sass. "Heat shock genes and the heat shock response in zebrafish embryos." Biochemistry and Cell Biology 75, no. 5 (October 1, 1997): 487–97. http://dx.doi.org/10.1139/o97-083.
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Heat shock genes exhibit complex patterns of spatial and temporal regulation during embryonic development in a wide range of organisms. Our laboratory has initiated an analysis of heat shock protein gene expression in the zebrafish, a model system that is now utilized extensively for the examination of early embryonic development of vertebrates. We have cloned members of the zebrafish hsp47, hsp70,\i and hsp90 gene families and shown them to be closely related to their counterparts in higher vertebrates. Whole mount in situ hybridization and Northern blot analyses have revealed that these genes are regulated in distinct spatial, temporal, and stress-specific manners. Furthermore, the tissue-specific expression patterns of the hsp47 and hsp90 alpha genes correlate closely with the expression of genes encoding known chaperone targets of Hsp47 and Hsp90 in other systems. The data raise a number of interesting questions regarding the function and regulation of these heat shock genes in zebrafish embryos during normal development and following exposure to environmental stress.
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Jiao, Shuyu, Chunyan Bai, Chunyun Qi, Heyong Wu, Lanxin Hu, Feng Li, Kang Yang, et al. "Identification and Functional Analysis of the Regulatory Elements in the pHSPA6 Promoter." Genes 13, no. 2 (January 21, 2022): 189. http://dx.doi.org/10.3390/genes13020189.
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Functional and expressional research of heat shock protein A6 (HSPA6) suggests that the gene is of great value for neurodegenerative diseases, biosensors, cancer, etc. Based on the important value of pigs in agriculture and biomedicine and to advance knowledge of this little-studied HSPA member, the stress-sensitive sites in porcine HSPA6 (pHSPA6) were investigated following different stresses. Here, two heat shock elements (HSEs) and a conserved region (CR) were identified in the pHSPA6 promoter by a CRISPR/Cas9-mediated precise gene editing strategy. Gene expression data showed that sequence disruption of these regions could significantly reduce the expression of pHSPA6 under heat stress. Stimulation studies indicated that these regions responded not only to heat stress but also to copper sulfate, MG132, and curcumin. Further mechanism studies showed that downregulated pHSPA6 could significantly affect some important members of the HSP family that are involved in HSP40, HSP70, and HSP90. Overall, our results provide a new approach for investigating gene expression and regulation that may contribute to gene regulatory mechanisms, drug target selection, and breeding stock selection.
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Pan, Jieli, Fusheng Jiang, Jia Zhou, Dehong Wu, Zhenhua Sheng, and Meiya Li. "HSP90: A Novel Target Gene of miRNA-628-3p in A549 Cells." BioMed Research International 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/4149707.
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Lung cancer is one of the leading causes of cancer-related death in the world. MicroRNA- (miR-) 628-3p plays critical roles in many cancers, including lung cancer. We investigated how miR-628-3p affected migration and apoptosis in A549 cells. We used bioinformatics algorithms to predict the miR-628-3p target gene to study the molecular mechanism by which miR-628-3p contributes to lung cancer. Then, we used the luciferase reporter assay to identify whether heat shock protein 90a (HSP90) is a direct target of miR-628-3p. Western blotting and quantitative real-time PCR showed that miR-628-3p downregulated HSP90a protein expression via a posttranscriptional mechanism. We confirm that miR-628-3p promotes apoptosis and inhibits migration in A549 cells by negatively regulating HSP90. Our results may reveal a novel strategy for lung cancer treatment.
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Avenatti, R. C., K. H. McKeever, D. W. Horohov, and K. Malinowski. "Effects of age and exercise on inflammatory cytokines, HSP70 and HSP90 gene expression and protein content in Standardbred horses." Comparative Exercise Physiology 14, no. 1 (February 23, 2018): 27–46. http://dx.doi.org/10.3920/cep170020.
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We hypothesised that the cortisol response to acute exercise, markers of oxidative stress, expression of inflammatory cytokines, heat shock protein (HSP)70 and HSP90 expression in whole blood and skeletal muscle, and HSP70 and HSP90 protein concentrations in skeletal muscle are altered by age and in response to acute submaximal exercise in horses. Young (n=6; 5.5±2.8 year) and aged (n=6; 22.6±2.25 year) unconditioned Standardbred mares underwent an acute submaximal exercise test. Blood samples were collected and analysed for plasma cortisol and malondialdehyde (MDA) concentrations, and for cytokine and HSP gene expression pre- and post-exercise. Gluteus medius biopsies were obtained for analysis of cytokine and HSP gene expression pre- and at 0, 4, 24 and 48 h post-exercise. Data were analysed for main effects using a two-way ANOVA for repeated measures. Post-hoc comparisons of means were conducted using Student-Neuman-Keuls for pair-wise multiple comparisons where appropriate. Acute submaximal exercise increased plasma cortisol concentration in both young and aged mares, and the duration of the post-exercise rise in cortisol was altered in aged horses. Plasma MDA concentration and expression of tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 were unchanged in blood and muscle. Exercise increased IL-1β expression in whole blood of young and aged mares, with young mares having greater exercise-induced expression at 2 (P<0.001) and 4 (P=0.019) h post-exercise. Both young and aged horses had increased HSP70 expression in whole blood following acute exercise, with young horses exhibiting 3-fold greater HSP70 expression than aged mares at 2 h post-exercise. HSP90 expression in whole blood following exercise was increased only in young horses. Both young and aged horses had increased HSP90 expression in skeletal muscle following exercise, but there was no difference due to age. However, the timing of HSP70 expression was different between young and aged horses. The age-related changes in cortisol and IL-1β expression following acute submaximal exercise can have implications for energy homeostasis and the adaption to such disturbances at a cellular and whole animal level. Quantification of HSP expression in whole blood may be a useful biomarker, with implications for cellular adaptation and survival in aged horses.
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Tetievsky, Anna, and Michal Horowitz. "Posttranslational modifications in histones underlie heat acclimation-mediated cytoprotective memory." Journal of Applied Physiology 109, no. 5 (November 2010): 1552–61. http://dx.doi.org/10.1152/japplphysiol.00469.2010.
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We have demonstrated that heat acclimation (AC) causes selective, long-lasting, transcriptional changes in cytoprotective and chromatin remodeling-associated genes, which maintain their AC transcriptome profile, despite the loss of the AC phenotype (Tetievsky et al. Physiol Genomics 34: 78–87, 2008). We postulated that AC memory involves upstream epigenetic information, which predisposes to rapid reacclimation (ReAC) and cytoprotective memory. Here we tested the hypothesis that posttranslational histone modifications are linked to this process. Rats subjected to AC (34°C for 2 or 30 days), deacclimation (DeAC; 24°C, 30 days), and ReAC (34°C, 2 days), and untreated controls were used. Histone H4 lysine acetylation and histone H3 acetylation and phosphorylation in the heat shock element (HSE) of the promoters of heat shock protein-70 ( hsp70) and -90 ( hsp90) genes were examined. Histone acetyltransferase recruitment of TIP60 (60-kDa histone acetyltransferase-interactive protein), the catalytic subunit of NuH4, was used to validate acetylation. Heat shock factor-1 (HSF-1)-HSE binding to the hsp70 and hsp90 genes was measured to confirm HSF-1 binding to euchromatin. Our results indicate that, while histone H3Ser10 phosphorylation occurred during the AC 2-day phase, AC constitutively elevated histone H4 acetylation in the HSE of hsp70 and hsp90 promoters. HSF-1-HSE binding was detected in the hsp70 gen e throughout AC-DeAC-ReAC. The hsp90 gene lacked HSF-1 binding during DeAC, but resumed a high binding level upon ReAC. HSP-90 is a critical cytoprotective protein, and the HSF-1- hsp90 binding profile matched levels of this protein. We conclude that, while early histone H3 phosphorylation is probably required for subsequent histone H4 acetylation, the constitutively acetylated histone H4 and the preserved euchromatin state throughout AC-DeAC-ReAC predispose to rapid cytoprotective acclimatory memory.
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Zhao, Rongmin, and Walid A. Houry. "Hsp90: a chaperone for protein folding and gene regulation." Biochemistry and Cell Biology 83, no. 6 (December 1, 2005): 703–10. http://dx.doi.org/10.1139/o05-158.
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Molecular chaperones are essential components of a quality control machinery present in the cell. They can either aid in the folding and maintenance of newly translated proteins, or they can lead to the degradation of misfolded and destabilized proteins. Hsp90 is a key member of this machinery. It is a ubiquitous molecular chaperone that is found in eubacteria and all branches of eukarya. It plays a central role in cellular signaling since it is essential for maintaining the activity of several signaling proteins, including steroid hormone receptors and protein kinases. Hsp90 is currently a novel anticancer drug target since it is overexpressed in some cancer cells. The chaperone typically functions as part of large complexes, which include other chaperones and essential cofactors that regulate its function. It is thought that different cofactors target Hsp90 to different sets of substrates. However, the mechanism of Hsp90 function remains poorly understood. As part of an effort to elucidate the Hsp90 chaperone network, we carried out a large-scale proteomics study to identify physical and genetic interactors of the chaperone. We identified 2 highly conserved novel Hsp90 cofactors, termed Tah1 and Pih1, that bind to the chaperone and that also associate physically and functionally with the essential DNA helicases Rvb1 and Rvb2. These helicases are key components of the chromatin remodeling complexes Ino80 and SWR-C. Tah1 and Pih1 seem to represent a novel class of Hsp90 cofactors that allow the chaperone to indirectly affect gene regulation in the cell in addition to its ability to directly promote protein folding. In this review, we provide an overview of Hsp90 structure and function, and we discuss the literature that links the chaperone activity to gene regulation.Key words: Hsp90, chaperone, cochaperone, gene regulation, protein folding.
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Kim, Donguk, Jaehyeon Jeong, Ji-Ae Ryu, Sa Rang Choi, Jung Myoung Lee, and Heeyoun Bunch. "In Vitro Evaluation of Lignin-Containing Nanocellulose." Materials 13, no. 15 (July 29, 2020): 3365. http://dx.doi.org/10.3390/ma13153365.
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The increasing importance of environmental sustainability has led to the development of new materials that are environmentally friendly, functional, and cost-effective. Lignin-containing cellulose nanomaterials are a common example of these. The advantages of lignocelluloses include their renewability, sustainability, and functionality combined with molecular rigidity and enhanced hydrophobicity. In order to valorize these beneficial traits from lignin-containing nanocellulose, various approaches have been examined in industrial applications. However, the safety of these materials has not been tested or validated in humans. In this study, we tested 21 wt% lignin-containing nanocellulose (L-MFC) in vitro using the human lung and kidney cell lines, H460 and HEK293 cells, respectively. The cytotoxicity of cellulose, L-MFC, and lignin was compared using the water-soluble tetrazolium salt assays. In addition, the gene expressions of HSP70 and HSP90 as cellular stress markers treated with cellulose, L-MFC, and lignin were quantified using real-time polymerase chain reaction (PCR) and Western blotting. Our data indicated little cytotoxicity for cellulose and significant cytotoxicity for lignin and a relatively low level of cytotoxicity for L-MFC, providing the lethal median concentration (LC50) values of L-MFC and lignin. The gene expression of HSP70 and HSP90 was little affected by moderate concentrations of L-MFC. Interestingly, the lignin contained in L-MFC influenced the cell viability and the gene expression of HSP70 and HSP90 less than the same amount of lignin alone. These results indicate that L-MFC displays cell-type-dependent sensitivity and suggest that L-MFC could serve as a new eco-friendly material that is relatively safe for humans.
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Bagchi, M. K., S. Y. Tsai, M. J. Tsai, and B. W. O'Malley. "Progesterone enhances target gene transcription by receptor free of heat shock proteins hsp90, hsp56, and hsp70." Molecular and Cellular Biology 11, no. 10 (October 1991): 4998–5004. http://dx.doi.org/10.1128/mcb.11.10.4998-5004.1991.
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Steroid receptors regulate transcription of target genes in vivo and in vitro in a steroid hormone-dependent manner. Unoccupied progesterone receptor exists in the low-salt homogenates of target cells as a functionally inactive 8 to 10S complex with several nonreceptor components such as two molecules of 90-kDa heat shock protein (hsp90), a 70-kDa heat shock protein (hsp70), and a 56-kDa heat shock protein (hsp56). Ligand-induced dissociation of receptor-associated proteins such as hsp90 has been proposed as the mechanism of receptor activation. Nevertheless, it has not been established whether, beyond release of heat shock proteins, the steroidal ligand plays a role in modulating receptor activity. To examine whether the release of these nonreceptor proteins from receptor complex results in a constitutively active receptor, we isolated an unliganded receptor form essentially free of hsp90, hsp70, and hsp56. Using a recently developed steroid hormone-responsive cell-free transcription system, we demonstrate for the first time that the dissociation of heat shock proteins is not sufficient to generate a functionally active receptor. This purified receptor still requires hormone for high-affinity binding to a progesterone response element and for efficient transcriptional activation of a target gene. When an antiprogestin, Ru486, is bound to the receptor, it fails to promote efficient transcription. We propose that in the cell, in addition to the release of receptor-associated inhibitory proteins, a distinct hormone-mediated activation event must precede efficient gene activation.
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Bagchi, M. K., S. Y. Tsai, M. J. Tsai, and B. W. O'Malley. "Progesterone enhances target gene transcription by receptor free of heat shock proteins hsp90, hsp56, and hsp70." Molecular and Cellular Biology 11, no. 10 (October 1991): 4998–5004. http://dx.doi.org/10.1128/mcb.11.10.4998.
Full textAbstract:
Steroid receptors regulate transcription of target genes in vivo and in vitro in a steroid hormone-dependent manner. Unoccupied progesterone receptor exists in the low-salt homogenates of target cells as a functionally inactive 8 to 10S complex with several nonreceptor components such as two molecules of 90-kDa heat shock protein (hsp90), a 70-kDa heat shock protein (hsp70), and a 56-kDa heat shock protein (hsp56). Ligand-induced dissociation of receptor-associated proteins such as hsp90 has been proposed as the mechanism of receptor activation. Nevertheless, it has not been established whether, beyond release of heat shock proteins, the steroidal ligand plays a role in modulating receptor activity. To examine whether the release of these nonreceptor proteins from receptor complex results in a constitutively active receptor, we isolated an unliganded receptor form essentially free of hsp90, hsp70, and hsp56. Using a recently developed steroid hormone-responsive cell-free transcription system, we demonstrate for the first time that the dissociation of heat shock proteins is not sufficient to generate a functionally active receptor. This purified receptor still requires hormone for high-affinity binding to a progesterone response element and for efficient transcriptional activation of a target gene. When an antiprogestin, Ru486, is bound to the receptor, it fails to promote efficient transcription. We propose that in the cell, in addition to the release of receptor-associated inhibitory proteins, a distinct hormone-mediated activation event must precede efficient gene activation.
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Wang, Haidong, Yudong Ba, Wenxiu Han, Haixia Zhang, Laiqing Zhu, and Pei Jiang. "Association of heat shock protein polymorphisms with patient susceptibility to coronary artery disease comorbid depression and anxiety in a Chinese population." PeerJ 9 (June 18, 2021): e11636. http://dx.doi.org/10.7717/peerj.11636.
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Background Coronary artery disease (CAD) is one of the severe diseases that threaten human health worldwide. In addition, the associated rate of comorbidity with depression and anxiety is extremely high. Heat shock proteins (HSPs) are a group of proteins that possesses cardiovascular and psychological protection properties. The objective of this study is to determine the association of the two most widely studied HSPs, namely, HSP70 and HSP90, with CAD comorbid depression and anxiety in a Chinese population. Methods A case-control study involving 271 CAD patients and 113 healthy individuals was conducted. The 271 CAD patients include individuals with (123) and without depression (148) and individuals with (57) and without anxiety (214). Ten single nucleotide polymorphisms (SNPs) for HSP70 and seven SNPs for HSP90 were selected and genotyped. Results Results revealed that the HSP70 rs10892958 C allele and HSP70 rs2236658 T allele were associated with a decreased risk of CAD (P < 0.05), whereas the G allele of the rs11218941 polymorphism was associated with an increased risk of CAD. The haplotype analysis results indicated that the haplotype TGGGC of the HSPA8 gene (coded the HSP70 family, rs4936770/rs4802/rs10892958/rs11218941/rs2236658) significantly increased the risk of CAD (P = 0.008). Among the patients with CAD, the carriers of the CC genotype for the HSP90 rs1042665 showed higher risks of anxiety than the carriers of another genotypes. However, no significant relationships were found among the CAD with depression and CAD without depression groups for the selected SNPs. These findings suggested that the genetic polymorphisms in the HSP gene, especially the HSPA8 of HSP70, contribute to CAD susceptibility and rs1042665 genetic polymorphisms might have an effect on the anxiety incidence among CAD patients.
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Orthwein, Alexandre, Anne-Marie Patenaude, El Bachir Affar, Alain Lamarre, Jason C. Young, and Javier M. Di Noia. "Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90." Journal of Experimental Medicine 207, no. 12 (November 1, 2010): 2751–65. http://dx.doi.org/10.1084/jem.20101321.
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Activation-induced deaminase (AID) is the mutator enzyme that initiates somatic hypermutation and isotype switching of the antibody genes in B lymphocytes. Undesired byproducts of AID function are oncogenic mutations. AID expression levels seem to correlate with the extent of its physiological and pathological functions. In this study, we identify AID as a novel Hsp90 (heat shock protein 90 kD) client. We find that cytoplasmic AID is in a dynamic equilibrium regulated by Hsp90. Hsp90 stabilizes cytoplasmic AID, as specific Hsp90 inhibition leads to cytoplasmic polyubiquitination and proteasomal degradation of AID. Consequently, Hsp90 inhibition results in a proportional reduction in antibody gene diversification and off-target mutation. This evolutionarily conserved regulatory mechanism determines the functional steady-state levels of AID in normal B cells and B cell lymphoma lines. Thus, Hsp90 assists AID-mediated antibody diversification by stabilizing AID. Hsp90 inhibition provides the first pharmacological means to down-regulate AID expression and activity, which could be relevant for therapy of some lymphomas and leukemias.
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Yasa, Ngurah Sedana, Lutfi Anshory, Niken S. N. Handayani, Alim Isnansetyo, and Murwantoko Murwantoko. "Pengaruh Paparan Chlorine terhadap Stress Fisiologis dan Ekspresi Gen Hsp70 dan Hsp90 pada Abalon (Haliotis squamata)." Buletin Oseanografi Marina 10, no. 3 (July 31, 2021): 223–32. http://dx.doi.org/10.14710/buloma.v10i3.35251.
Full textAbstract:
Abalon merupakan salah satu moluska bercangkang tunggal yang memiliki nilai ekonomis tinggi dan merupakan komoditas potensial dalam peningkatan devisa Negara. Namun permasalahannya adalah mudahnya abalone mengalami stress akibat perubahan berbagai faktor lingkungan seperti suhu, salinitas, bakteri Vibrio dan bahan desinfektan seperti chlorine. Penelitian ini dilakukan untuk mengetahui tingkat stress benih abalone terhadap paparan chlorine pada gen heat shock protein (HSP) dan mengetahui perubahan enzim-enzim antioksidan seperti SOD,CAT,PO dan perubahan struktur histologi otot kaki abalone akibat paparan chlorine. Koleksi benih abalone dengan ukuran cangkang 3-4 cm dari unit hatchery abalone, BPIU2K Karangasem Bali. Uji paparan abalone pada akuarium kaca volume 100 L dengan konsentrasi chlorine 10 ppm. Pengambilan sample (hemolim, otot kaki, gonad) dilakukan pada waktu pengamatan (0,12,24,48 jam). Pengamatan meliputi uji ekspresi gen heat shock protein (Hsp70 dan Hsp90), aktifitas enzim-enzim antioksidan dan histology pada otot kaki. Hasil penelitian menunjukkan bahwa Hsp70 terekspresi paling tinggi pada hemolim abalone yaitu sebesar 350 kali lipat pada paparan jam ke 12 dibandingkan kontrol (P<0.05). Sedangkan, Hsp90 pada waktu yang sama menunjukkan tingkat stress abalone paling tinggi pada otot kaki dengan tingkat ekspresi sebesar 7 kali lipat jika dibandingkan kontrol (P<0.05). Gen heat shock protein diekspresikan cukup tinggi pada uji paparan chlorine, namun demikian Hsp70 menunjukkan tingkat ekspresi yang lebih tinggi jika dibanding dengan Hsp90. Hsp70 lebih sensitif sebagai marka stress abalone akibat paparan chlorine. Perubahan struktur histologi menunjukkan cemaran chlorine dapat meningkatkan ukuran diameter hemolim sinus dan kerusakan pada lapisan epithel otot kaki abalone. Abalone is one of the single-shelled mollusks which has high economic value and is a commodity in increasing the country's foreign exchange. However, the problem is that it is easy for abalone to experience stress due to the influence of various environmental factors such as temperature, salinity, Vibrio bacteria and disinfectants such as chlorine. The study was conducted to determine the stress level of abalone seeds produced by hatcheries against residual chlorine. The aim of the study were to see the stress level based on the heat shock protein (HSP) gene and to see changes in antioxidant enzymes such as SOD, CAT, PO and histological structure of abalone foot muscles due to chlorine contamination. Collection of abalone seeds with a 3-4 cm shell size from the abalone hatchery unit, BPIU2K Karangasem Bali. Abalone exposure test using a glass volume of 100 L with a chlorine concentration of 10 ppm. Furthermore, sampling was carried out (hemolime, leg muscles, gonads) at the time of observation (0.12,24,48 hours). Observations included heat shock protein gene expression (Hsp70 and Hsp90) and histology in foot muscles. The results showed that Hsp70 was the highest expressed in hemolime abalone 350 times at 12 hours exposure compared to controls (P <0.05). Meanwhile, Hsp90 at the same time showed the highest level of stress on leg muscles with an expression level of 7 times when compared to controls (P <0.05). It was concluded that the heat shock protein gene was expressed high enough in the chlorine exposure test, however, Hsp70 was more sensitive as a sign of abalone stress as indicated by a higher expression level when compared to Hsp90. Changes in the histological structure show that chlorine contamination can increase the diameter of the sinus hemolime and damage to the epithelial layer of the abalone foot muscles.
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Jiménez-Canino, Rubén, Fabián Lorenzo-Díaz, Frederic Jaisser, Nicolette Farman, Teresa Giraldez, and Diego Alvarez de la Rosa. "Histone Deacetylase 6–Controlled Hsp90 Acetylation Significantly Alters Mineralocorticoid Receptor Subcellular Dynamics But Not its Transcriptional Activity." Endocrinology 157, no. 6 (April 21, 2016): 2515–32. http://dx.doi.org/10.1210/en.2015-2055.
Full textAbstract:
The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis, and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein (Hsp) 90), Hsp70, and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and -independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or nonacetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast with the down-regulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell.
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Kim, Won-Seob, Jalil Ghassemi Nejad, Sang-Gun Roh, and Hong-Gu Lee. "Heat-Shock Proteins Gene Expression in Peripheral Blood Mononuclear Cells as an Indicator of Heat Stress in Beef Calves." Animals 10, no. 5 (May 21, 2020): 895. http://dx.doi.org/10.3390/ani10050895.
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This study was conducted to investigate the effect of HS on HSPs gene expression in bovine PBMCs of beef calves in in vitro and in vivo models. In the in vitro experiment, blood samples were collected from the jugular vein of five beef calves (age: 174.2 ± 5.20 days, BW: 145.2 ± 5.21 kg). In the in vivo experiment, sixteen Korean native male beef calves (age: 169.6 ± 4.60 days, BW: 136.9 ± 6.23 kg) were exposed to ambient temperature for seven days (22 to 24 °C, relative humidity 60%; temperature–humidity index (THI) = 68 to 70) and subsequently to the temperature and humidity corresponding to the target THI level for 21 days (HS). For PBMC isolation, blood samples were collected every three days. In the in vitro model, the cell viability was significantly decreased in HS groups compared with the control group (p = 0.015). The expression of HSP70 (p = 0.022), HSP90 (p = 0.003) and HSPB1 (p = 0.026) genes was increased in the HS group in in vitro model. In the in vivo experiment, the HSP70 gene expression was increased after sudden exposure to HS conditions (severe THI levels; THI = 88 to 90), whereas HSP90 and HSPB1 showed no differences among the THI groups (p > 0.05). However, in the severe THI group, the HSP70 gene expression returned to normal range after six days of continuous HS. In conclusion, the HSP70 gene plays a pivotal role in protecting cells from damage and is sensitive to HS in immune cells compared with other HSP genes in in vitro and in vivo models. In addition, the in vivo models suggest that calves exhibit active physiological mechanisms of adaptation to HS after six days of continuous exposure by regulating the HSP70 gene expression.
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Bar-Lavan, Yael, Netta Shemesh, and Anat Ben-Zvi. "Chaperone families and interactions in metazoa." Essays in Biochemistry 60, no. 2 (October 15, 2016): 237–53. http://dx.doi.org/10.1042/ebc20160004.
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Quality control is an essential aspect of cellular function, with protein folding quality control being carried out by molecular chaperones, a diverse group of highly conserved proteins that specifically identify misfolded conformations. Molecular chaperones are thus required to support proteins affected by expressed polymorphisms, mutations, intrinsic errors in gene expression, chronic insult or the acute effects of the environment, all of which contribute to a flux of metastable proteins. In this article, we review the four main chaperone families in metazoans, namely Hsp60 (where Hsp is heat-shock protein), Hsp70, Hsp90 and sHsps (small heat-shock proteins), as well as their co-chaperones. Specifically, we consider the structural and functional characteristics of each family and discuss current models that attempt to explain how chaperones recognize and act together to protect or recover aberrant proteins.
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Alford, Brian D., and Onn Brandman. "Quantification of Hsp90 availability reveals differential coupling to the heat shock response." Journal of Cell Biology 217, no. 11 (August 21, 2018): 3809–16. http://dx.doi.org/10.1083/jcb.201803127.
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The heat shock response (HSR) is a protective gene expression program that is activated by conditions that cause proteotoxic stress. While it has been suggested that the availability of free chaperones regulates the HSR, chaperone availability and the HSR have never been precisely quantified in tandem under stress conditions. Thus, how the availability of chaperones changes in stress conditions and the extent to which these changes drive the HSR are unknown. In this study, we quantified Hsp90 chaperone availability and the HSR under multiple stressors. We show that Hsp90-dependent and -independent pathways both regulate the HSR, and the contribution of each pathway varies greatly depending on the stressor. Moreover, stressors that regulate the HSR independently of Hsp90 availability do so through the Hsp70 chaperone. Thus, the HSR responds to diverse defects in protein quality by monitoring the state of multiple chaperone systems independently.
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Laskar, Shyamasree, Mrinal K. Bhattacharyya, Rama Shankar, and Sunanda Bhattacharyya. "HSP90 Controls SIR2 Mediated Gene Silencing." PLoS ONE 6, no. 8 (August 4, 2011): e23406. http://dx.doi.org/10.1371/journal.pone.0023406.
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Ncho, Chris Major, Akshat Goel, Vaishali Gupta, Chae-Mi Jeong, and Yang-Ho Choi. "Embryonic manipulations modulate differential expressions of heat shock protein, fatty acid metabolism, and antioxidant-related genes in the liver of heat-stressed broilers." PLOS ONE 17, no. 7 (July 15, 2022): e0269748. http://dx.doi.org/10.1371/journal.pone.0269748.
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In this study, the effects of in ovo feeding of γ-aminobutyric acid (GABA) and embryonic thermal manipulation (TM) on plasma biochemical parameters, organ weights, and hepatic gene expression in broilers exposed to cyclic heat stress (32 ± 1°C for 8 days) (HS) were investigated. A total of 175 chicks were assigned to five treatments: chicks hatched from control eggs (CON); chicks hatched from control eggs but exposed to HS (CON+HS); chicks hatched from eggs injected at 17.5 days of incubation with 0.6mL of 10% GABA and exposed to HS (G10+HS); chicks hatched from thermally manipulated eggs (39.6°C, 6h/d from embryonic days 10 to 18) and exposed to HS (TM+HS); chicks hatched from eggs that received both previous treatments during incubation and exposed to HS (G10+TM+HS). Results revealed that on day 36 post-hatch, hepatic NADPH oxidase 1 (P = 0.034) and 4 (P = 0.021) genes were downregulated in the TM+HS and G10+TM+HS compared to the CON+HS group. In addition, while acetyl-CoA carboxylase gene expression was reduced (P = 0.002) in the G10+TM group, gene expression of extracellular fatty acid-binding protein and peroxisome proliferator-activated receptor-γ was lower (P = 0.045) in the TM+HS group than in the CON+HS group. HS led to higher gene expression of heat shock protein 70 (HSP70) and 90 (HSP90) (P = 0.005, and P = 0.022). On the other hand, the TM+HS group exhibited lower expression of both HSP70 (P = 0.031) and HSP90 (P = 0.043) whereas the G10+TM+HS group had a reduced (P = 0.016) HSP90 expression compared to the CON+HS. MANOVA on different gene sets highlighted an overall lower (P = 0.034) oxidative stress and lower (P = 0.035) heat shock protein expression in the G10+TM+HS group compared to the CON+HS group. Taken together, the current results suggest that the combination of in ovo feeding of GABA with TM can modulate HSPs and antioxidant-related gene expression in heat-stressed broilers.
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Gonzalez, Mariana Selena, Carlos Daniel De Brasi, Michele Bianchini, Cristian Ferri, Raquel Bengió, and Irene Beatriz Larripa. "Expression of CAMKIIγ, HSP70 and HSP90 Genes Are Differentially Associated with the Mutational Status of Tirosine Kinase Domain in Chronic Myeloid Leukemia Resistant Patients." Blood 118, no. 21 (November 18, 2011): 4877. http://dx.doi.org/10.1182/blood.v118.21.4877.4877.
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Abstract Abstract 4877 Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the reciprocal chromosomal translocation between chromosome 9 and 22, t(9;22)(q34;q11), known as Philadelphia chromosome. At molecular level, this cytogenetic aberration associates with a chimeric BCR-ABL fusion gene responsible for the pathogenesis of the disease. Targeting BCR-ABL with tyrosine kinase inhibitors (TKIs) has led to a rapid clinical response in most CML cases; however, harboring of point mutations within the kinase domain (KD) of BCR-ABL is the most common mechanism responsible for acquired resistance to therapy. The objective of this work was to evaluate the expression profiles of 4 different genes involved in proliferation, differentiation or cell survival, in order to study their association with acquired missense mutations within the KD of BCR-ABL. Due to its clear involvement in cell proliferation and apotosis the following genes were analyzed. CAMKIIγ (Ca2+ /calmodulin dependent protein kinase IIγ) is a critical regulator of multiple signalling networks regulating the proliferation in myeloid leukaemia. HSP70 (Heat Shock protein 70) is a chaperone protein that protects cells from apoptotic and necrotic stimuli. HSP90 (Heat Shock protein 90) is a chaperone that facilitates folding of client proteins such as BCR-ABL. Ki-67 is a nuclear antigen associated with cellular proliferation and ribosomal RNA transcription. Total RNA was extracted from 50 TKI-resistant CML-patient's PBMC samples; by quantitative real time-PCR (QRT-PCR) (SybrGreen method, melting analysis and β2-microglobulin as an endogenous control reference gene) we measured the gene expression of CaMKIIγ, Ki67, HSP70, HSP90 and BCR-ABL. All patients were treated with TKIs (26 imatinib, 13 nilotinib, 11 dasatinib) and showed primary lack or loss of haematological and/or cytogenetic response according to the ELN (European Leukaemia Net) criteria. To characterize TKI-resistant mutations within the KD of the chimeric BCR-ABL gene, ABL exons 4, 5, 6 and 7 were subjected to automated DNA sequencing following a nested- BCR-ABL-specific PCR. Mutations were observed in 27/50 cases at 15 different residues: 1 L248V, 1 G250E, 1 Y253H, 5 E255K/V, 1 E279K, 1 V289F, 4 T315I, 2 F317L, 1 L348M, 3 M351T, 1 E355G, 1 N358S, 2 F359V/C, 2 L387M and 1 L389V. Remaining 23 CML cases did not show mutations (detection limit 10–20%). Our results showed a significant increase in the expression of CaMKIIγ and HSP70 and decrease of HSP90 in mutated patients (MT) with respect to cases without mutations (WT) (p<0.01). On the contrary, transcript levels of Ki67 and BCR-ABL did not show significant differences between MT and WT, likely due to the resistant status of both groups. Taking into account these results we design a score (TKI-MT) to estimate the likelihoods for a patient to harbor TKI-resistance mutations using the transcript normalised expression of CaMKIIγ, HSP70 and HSP90 as follows: [Log10(CaMKIIγ) + Log10(HSP70) – Log10(HSP90)]. TKI-MT scores from 27 and 23 patients from the MT and WT groups respectively were analysed by use of ROC curves in order to find an optimal cut-off value to classify new unstudied cases. We found that patients with TKI-MT scores over a cut-off value of −0.79 showed 4.8 times more probabilities to present TKI-resistance mutations than those below −0.79 (OR 4.8, CI95% 1.3–17.6, P<0.02). We concluded that the expression of CaMKIIγ, HSP70 and HSP90 allowed prediction of mutations in the ABL tyrosine kinase domain with 82% of specificity in CML patients treated with TKIs and associated with lack or loss of response. Disclosures: No relevant conflicts of interest to declare.
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Forafonov, Fedor, Oyetunji A. Toogun, Iwona Grad, Elena Suslova, Brian C. Freeman, and Didier Picard. "p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity." Molecular and Cellular Biology 28, no. 10 (March 24, 2008): 3446–56. http://dx.doi.org/10.1128/mcb.02246-07.
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ABSTRACT The molecular chaperone Hsp90 assists a subset of cellular proteins and is essential in eukaryotes. A cohort of cochaperones contributes to and regulates the multicomponent Hsp90 machine. Unlike the biochemical activities of the cochaperone p23, its in vivo functions and the structure-function relationship remain poorly understood, even in the genetically tractable model organism Saccharomyces cerevisiae. The SBA1 gene that encodes the p23 ortholog in this species is not an essential gene. We found that in the absence of p23/Sba1p, yeast and mammalian cells are hypersensitive to Hsp90 inhibitors. This protective function of Sba1p depends on its abilities to bind Hsp90 and to block the Hsp90 ATPase and inhibitor binding. In contrast, the protective function of Sba1p does not require the Hsp90-independent molecular chaperone activity of Sba1p. The structure-function analysis suggests that Sba1p undergoes considerable structural rearrangements upon binding Hsp90 and that the large size of the p23/Sba1p-Hsp90 interaction surface facilitates maintenance of high affinity despite sequence divergence during evolution. The large interface may also contribute to preserving a protective function in an environment in which Hsp90 inhibitory compounds can be produced by various microorganisms.
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Hung, Jan-Jong, Che-Sheng Chung, and Wen Chang. "Molecular Chaperone Hsp90 Is Important for Vaccinia Virus Growth in Cells." Journal of Virology 76, no. 3 (February 1, 2002): 1379–90. http://dx.doi.org/10.1128/jvi.76.3.1379-1390.2002.
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ABSTRACTMolecular chaperones assist protein folding, and some chaperones are induced by heat, nutrient depletion, or pathogen invasion. This study investigates the role played by Hsp90 in the life cycle of vaccinia virus. The titer of vaccinia intracellular mature virions (IMV) was reduced by 2 orders of magnitude in RK13 cells treated with geldanamycin (GA), which blocks the ATPase activity of Hsp90. GA does not affect expression from the viral early promoter, but treatment with GA delays DNA replication and intermediate gene transcription and reduces expression from the viral late promoter. Vaccinia virus infection does not induce Hsp90 expression; however, intracellular distribution of Hsp90 is altered in virus-infected cells. Hsp90 is restricted to the cytoplasm of mock-infected cells; in contrast, Hsp90 is transiently associated with virosomes in virus-infected cells although it is not incorporated into IMV. In addition, Hsp90 interacts with viral core protein 4a, the mature form of the A10L gene product, in virus-infected cells. In conclusion, these results suggest that a cellular chaperone protein, Hsp90, is important for vaccinia virus growth in cultured cells and that viral core protein 4a associates with Hsp90-containing complexes in the infected cells.
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SABBAH, Michèle, Christine RADANYI, Gérard REDEUILH, and Etienne-Emile BAULIEU. "The 90 kDa heat-shock protein (hsp90) modulates the binding of the oestrogen receptor to its cognate DNA." Biochemical Journal 314, no. 1 (February 15, 1996): 205–13. http://dx.doi.org/10.1042/bj3140205.
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The role of heat-shock protein 90 (hsp90) in the regulation of the oestrogen receptor (ER) function is less well understood than for other steroid-hormone receptors because hsp90 is not involved in the stabilization or induction of a high-affinity ligand-binding state of ER nor in the inhibition of receptor dimerization. Electrophoretic mobility-shift assays, using purified ER and hsp90, were employed to investigate directly the effect of hsp90 on the ability of ER to bind to the oestrogen-response element (ERE) from the vitellogenin A2 gene. Contrary to models in which hsp90 binds to and passively inactivates steroid-hormone receptors, our studies show that the binding of ER to ERE is inversely dependent on the relative concentration of hsp90. Exposure of purified ER–hsp90 complexes to ERE led to the dissociation of hsp90 and concomitant specific binding of ER to ERE. We demonstrate that the amount of ER–ERE complex decreased with increasing concentrations of hsp90. Furthermore hsp90 dissociated preformed high-affinity ER–ERE complexes. Kinetic dissociation experiments indicate that hsp90 acts in a dynamic and specific process rather than by simple trapping of ER owing to its inherent off-rate. The receptor released from the ERE-bound state by hsp90 was recovered associated with hsp90 and was able to rebind to ERE. These results indicate that hsp90 does not suppress ER function merely by steric hindrance. On the basis of these results and others, we propose that, in vivo, hsp90 may play a dual role in ER function: (i) at a physiological temperature, hsp90 stabilizes an active form of the receptor in accordance with its general molecular chaperone role; (ii) at elevated temperatures or under other environmental stress, the increased cellular concentration of hsp90 negatively interferes with ER-dependent transcription, in accordance with the inhibition of gene transcription attributed to hsp90 after heat shock.
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Zhang, Xiaohong, Jianrong Sun, Rongzhen Xu, Zhiwen He, and Yin Gu. "Roles of Phosphorylated p210bcr/abl and Hsp90 Protein in Apoptosis Induced by Berbamine in K562 Cells." Blood 108, no. 11 (November 16, 2006): 4418. http://dx.doi.org/10.1182/blood.v108.11.4418.4418.
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Abstract Chronic myeloid leukemia (CML) is a pluripotent hematopoietic stem cell disorder characterized by accumulation of mature and immature granulocytes in peripheral blood and bone marrow due to uncontrolled growth and resistance to apoptosis. The dysregulated activity of the bcr/abl oncoprotein tyrosine kinase, which is encoded by the bcr-abl fusion gene generated from the chromosomal translocation of t(9; 22) and present in approximately 95% of CML patients, has been shown to be responsible for these malignant phenotypes. Numerous studies have demonstrated that only being phosphorylated that p210bcr/abl oncoprotein can promote cell proliferation and survival, and block apoptosis of tumor cells. Bcr/abl tyrosine kinase has chaperone association with heat shock protein 90 (Hsp90), which plays an essential role in stabilization of bcr/abl protein. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevecsensitive and -resistant Ph+ CML cells, but little is known about its exact mechanisms. We investigated the the expression levels of phosphorylated p210bcr/abl protein and Hsp90 protein in apoptosis induced by berbamine in K562 cells by means of various technologies, including cell culture system, flow cytomerty, western blot and immunoprecipitation (IP). Methods: Human Ph+ CML leukemia K562 cells, which express endogenous p210bcr/abl protein, were cultured in RPMI 1640 and treated with berbamine as indicated time and dose. Flow cytometry (FCM) and Annexin V-FLUOS/PI staining kit were used to evaluate apoptosis of leukemic cells; FCM and cytoperm/cytofix plus Caspase-3-McAb-PE were employed to measure leukemic cells with activated Caspase-3. Phosphorylation of p210bcr/abl protein in leukemic cells were assessed by a combination of immunoprecipitation (IP) with c-abl antibody and Western blot with p-Tyr(pY99)antibody. The protein levels of P210bcr/abl, Hsp90 and Hsp70 in leukemic cells were determined by Western blot with antibodies to c-abl, Hsp90 and Hsp70, respectively. Results: After treatment with berbamine at 8 μg/ml for 48 h, the percentages of leukemic cells expressing activated caspase-3 and apoptotic cells were 45.69% and 48.43%, respectively. IP and WB results showed that berbamine at low concentration markedly inhibited phosphorylation of p210bcr/abl protein in leukemia cells, and the amount of phosphorylated p210bcr/abl in leukemia cells exposured to berbamine at 8 μg/ml for 6 h were only 8.41% of that of untreated leukemia cells without the protein levels of P210bcr/abl down-regulated. Berbamine also down-regulated chaperone Hsp90 protein, and the amount of Hsp90 protein in leukemia cells treated with berbamine at 8 μg/ml for 48 h accounted for 18.37% of that of untreated leukemia cells. Interestingly, berbamine at 8 μg/ml had no obvious effects on chaperone Hsp70 protein expression associated with the resistance of leukemia cells to apoptosis. Conclusions: Berbamine could induce caspase-3-mediated apoptosis of Ph+ leukemia cells through inhibiting phosphorylation of p210bcr/abl protein and down-regulating its chaperone Hsp90 protein. Unlike Hsp90 inhibitor GA that could upregulate Hsp70, berbamine had no obvious effects on chaperone Hsp70 protein expression in leukemia cells, suggesting that berbamine may be a novel class of Hsp90 inhibitor, and further study is required.
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Deng, Yunyan, Fengting Li, Zhangxi Hu, Caixia Yue, and Ying Zhong Tang. "Expression Patterns of the Heat Shock Protein 90 (Hsp90) Gene Suggest Its Possible Involvement in Maintaining the Dormancy of Dinoflagellate Resting Cysts." International Journal of Molecular Sciences 22, no. 20 (October 13, 2021): 11054. http://dx.doi.org/10.3390/ijms222011054.
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Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone functioning in cellular structural folding and conformational integrity maintenance and thus plays vital roles in a variety of biological processes. However, many aspects of these functions and processes remain to be fully elucidated, particularly for non-model organisms. Dinoflagellates are a group of eukaryotes that are exceedingly important in primary production and are responsible for the most harmful algal blooms (HABs) in aquatic ecosystems. The success of dinoflagellates in dominating the plankton community is undoubtedly pertinent to their remarkable adaptive strategies, characteristic of resting cyst production and broad tolerance to stresses of temperature and others. Therefore, this study was conducted to examine the putative roles of Hsp90 in the acclimation to temperature stress and life stage alterations of dinoflagellates. Firstly, we isolated the full-length cDNA of an Hsp90 gene (StHsp90) via RACE from the cosmopolitan HAB species Scrippsiella trochoidea and tracked its transcriptions in response to varied scenarios via real-time qPCR. The results indicated that StHsp90 displayed significant mRNA augment patterns, escalating during 180-min treatments, when the cells were exposed to elevated and lowered temperatures. Secondly, we observed prominently elevated StHsp90 transcriptions in the cysts that were stored at the cold and dark conditions compared to those in newly formed resting cysts and vegetative cells. Finally, and perhaps most importantly, we identified 29 entries of Hsp90-encoding genes with complete coding regions from a dinoflagellate-specific environmental cDNA library generated from marine sediment assemblages. The observed active transcription of these genes in sediment-buried resting cysts was fully supported by the qPCR results for the cold-stored resting cysts of S. trochoidea. Hsp90s expressions in both laboratory-raised and field-collected cysts collectively highlighted the possible involvement and engagement of Hsp90 chaperones in the resting stage persistence of dinoflagellates.
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Deng, Yunyan, Fengting Li, Zhangxi Hu, Caixia Yue, and Ying Zhong Tang. "Expression Patterns of the Heat Shock Protein 90 (Hsp90) Gene Suggest Its Possible Involvement in Maintaining the Dormancy of Dinoflagellate Resting Cysts." International Journal of Molecular Sciences 22, no. 20 (October 13, 2021): 11054. http://dx.doi.org/10.3390/ijms222011054.
Full textAbstract:
Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone functioning in cellular structural folding and conformational integrity maintenance and thus plays vital roles in a variety of biological processes. However, many aspects of these functions and processes remain to be fully elucidated, particularly for non-model organisms. Dinoflagellates are a group of eukaryotes that are exceedingly important in primary production and are responsible for the most harmful algal blooms (HABs) in aquatic ecosystems. The success of dinoflagellates in dominating the plankton community is undoubtedly pertinent to their remarkable adaptive strategies, characteristic of resting cyst production and broad tolerance to stresses of temperature and others. Therefore, this study was conducted to examine the putative roles of Hsp90 in the acclimation to temperature stress and life stage alterations of dinoflagellates. Firstly, we isolated the full-length cDNA of an Hsp90 gene (StHsp90) via RACE from the cosmopolitan HAB species Scrippsiella trochoidea and tracked its transcriptions in response to varied scenarios via real-time qPCR. The results indicated that StHsp90 displayed significant mRNA augment patterns, escalating during 180-min treatments, when the cells were exposed to elevated and lowered temperatures. Secondly, we observed prominently elevated StHsp90 transcriptions in the cysts that were stored at the cold and dark conditions compared to those in newly formed resting cysts and vegetative cells. Finally, and perhaps most importantly, we identified 29 entries of Hsp90-encoding genes with complete coding regions from a dinoflagellate-specific environmental cDNA library generated from marine sediment assemblages. The observed active transcription of these genes in sediment-buried resting cysts was fully supported by the qPCR results for the cold-stored resting cysts of S. trochoidea. Hsp90s expressions in both laboratory-raised and field-collected cysts collectively highlighted the possible involvement and engagement of Hsp90 chaperones in the resting stage persistence of dinoflagellates.
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Pascual, Susana, Clara I. Rodríguez-Álvarez, Isgouhi Kaloshian, and Gloria Nombela. "Hsp90 Gene Is Required for Mi-1-Mediated Resistance of Tomato to the Whitefly Bemisia tabaci." Plants 12, no. 3 (February 1, 2023): 641. http://dx.doi.org/10.3390/plants12030641.
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The Mi-1 gene of tomato (Solanum lycopersicum) confers resistance against some nematodes and insects, but the resistance mechanisms differ depending on the harmful organism, as a hypersensitive reaction (HR) occurs only in the case of nematodes. The gene Rme1 is required for Mi-1-mediated resistance to nematodes, aphids, and whiteflies, and several additional proteins also play a role in this resistance. Among them, the involvement of the chaperone HSP90 has been demonstrated in Mi-1-mediated resistance for aphids and nematodes, but not for whiteflies. In this work, we studied the implication of the Hsp90 gene in the Mi-1 resistance against the whitefly Bemisia tabaci by means of Tobacco rattle virus (TRV)-based virus-induced gene silencing (VIGS). The silencing of the Hsp90 gene in tomato Motelle plants carrying the Mi-1 gene resulted in a decrease in resistance to whiteflies, as oviposition values were significantly higher than those on non-silenced plants. This decrease in resistance was equivalent to that caused by the silencing of the Mi-1 gene itself. Infiltration with the control TRV vector did not alter Mi-1 mediated resistance to B. tabaci. Similar to the Mi-1 gene, silencing of Hsp90-1 occurs partially, as silenced plants showed a significant but not complete suppression of gene expression. Thus, our results demonstrate the requirement of Hsp90 in the Mi-1-mediated resistance to B. tabaci and reinforce the hypothesis of a common model for this resistance to nematodes and insects.
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Wang, Yan, Min Huang, Peng Gao, Hao Chen, Yu Zheng, Chenming Yang, Zhirong Yang, and Qun Sun. "Expression of heat shock protein (HSP) genes and antioxidant enzyme genes in hybrid rice II YOU 838 during heat stress." Special Issue 2021, no. 15(09):2021 (September 10, 2021): 38–43. http://dx.doi.org/10.21475/ajcs.21.15.09.sp-4.
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II YOU 838 (Oryza sativa subsp. indica), crossed by the maternal II-32A and paternal Fu Hui 838, was one of the most widely cultivated hybrid rice in China. Fu Hui 838, which has resistance to high temperature, was generated by mutation technology in 1990. Previous field-testing showed that II YOU 838 had tolerance to high temperature stress and this was confirmed in the present study. The mechanism of heat tolerance of II YOU 838 is not understood. The present study reports gene expression of a representative sample of heat-responsive proteins in II YOU 838 flag leaves subjected to heat stress during flowering. Differential expression of the heat shock protein 70 (HSP70), heat shock protein 90 (HSP90), small heat shock protein (smHSP), superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) were studied under heat stress and optimum temperatures in flag leaves of II YOU 838. All six genes studied were responsive to high temperatures. Quantitative real-time PCR showed increased expression of the heat shock protein genes and antioxidant enzyme genes in flag leaves under heat stress. With increasing number of days gene expression decreased under high temperature. Peak expression of SOD, POD, hsp70 and hsp90 was on Day 2 under 39 ℃. On Day 3, the expression of CAT under 39 ℃ was the highest. The expression of smhsp was highest on Day 3 under 27 ℃, followed by that on Day 2 under 27 ℃. The maximum expression values were observed on Day 2 or Day 3 after beginning of heat stress. This suggests that hsp90, hsp70, SOD and POD are principally involved in early responses to heat in rice flag leaves, and that smhsp may play a role in the recovery mechanism in rice after heat stress. This may provide insights into the mechanism of heat-tolerance in rice
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Ojima, Koichi, Emi Ichimura, Takahiro Suzuki, Mika Oe, Susumu Muroya, and Takanori Nishimura. "HSP90 modulates the myosin replacement rate in myofibrils." American Journal of Physiology-Cell Physiology 315, no. 1 (July 1, 2018): C104—C114. http://dx.doi.org/10.1152/ajpcell.00245.2017.
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Myosin is a major myofibrillar component in skeletal muscles. In myofibrils, ~300 myosin molecules form a single thick filament in which there is constant turnover of myosin. Our previous study demonstrated that the myosin replacement rate is reduced by inhibition of protein synthesis (Ojima K, Ichimura E, Yasukawa Y, Wakamatsu J, Nishimura T, Am J Physiol Cell Physiol 309: C669–C679, 2015); however, additional factors influencing myosin replacement were unknown. Here, we showed that rapid myosin replacement requires heat shock protein 90 (HSP90) activity. We utilized the fluorescence recovery after photobleaching technique to measure the replacement rate of green fluorescent protein-fused myosin heavy chain (GFP-MYH) in myotubes overexpressing HSP90. Intriguingly, the myosin replacement rate was significantly increased in HSP90-overexpressing myotubes, whereas the myosin replacement rate slowed markedly in the presence of an HSP90-specific inhibitor, indicating that HSP90 activity promotes myosin replacement. To determine the mechanism of this effect, we investigated whether HSP90 activity increased the amount of myosin available for incorporation into myofibrils. Strikingly, the gene expression levels of MYHs were significantly elevated by HSP90 overexpression but downregulated by inhibition of HSP90 activity. Cytosolic myosin content was also increased in myotubes overexpressing HSP90. Taken together, our results demonstrate that HSP90 activity facilitates myosin replacement by upregulating MYH gene expression and thereby increasing cytosolic myosin content.
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Jeffery, Constance J. "Protein moonlighting: what is it, and why is it important?" Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1738 (December 4, 2017): 20160523. http://dx.doi.org/10.1098/rstb.2016.0523.
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Members of the GroEL/HSP60 protein family have been studied for many years because of their critical roles as ATP-dependent molecular chaperones, so it might come as a surprise that some have important functions in ATP-poor conditions, for example, when secreted outside the cell. At least some members of each of the HSP10, HSP70, HSP90, HSP100 and HSP110 heat shock protein families are also ‘moonlighting proteins’. Moonlighting proteins exhibit more than one physiologically relevant biochemical or biophysical function within one polypeptide chain. In this class of multifunctional proteins, the multiple functions are not due to gene fusions or multiple proteolytic fragments. Several hundred moonlighting proteins have been identified, and they include a diverse set of proteins with a large variety of functions. Some participate in multiple biochemical processes by using an active site pocket for catalysis and a different part of the protein's surface to interact with other proteins. Moonlighting proteins play a central role in many diseases, and the development of novel treatments would be aided by more information addressing current questions, for example, how some are targeted to multiple cellular locations and how a single function can be targeted by therapeutics without targeting a function not involved in disease. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
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Mandal, Atin K., Nadinath B. Nillegoda, Jennifer A. Chen, and Avrom J. Caplan. "Ydj1 Protects Nascent Protein Kinases from Degradation and Controls the Rate of Their Maturation." Molecular and Cellular Biology 28, no. 13 (April 28, 2008): 4434–44. http://dx.doi.org/10.1128/mcb.00543-08.
Full textAbstract:
ABSTRACT Ydj1 is a Saccharomyces cerevisiae Hsp40 molecular chaperone that functions with Hsp70 to promote polypeptide folding. We identified Ydj1 as being important for maintaining steady-state levels of protein kinases after screening several chaperones and cochaperones in gene deletion mutant strains. Pulse-chase analyses revealed that a portion of Tpk2 kinase was degraded shortly after synthesis in a ydj1Δ mutant, while the remainder was capable of maturing but with reduced kinetics compared to the wild type. Cdc28 maturation was also delayed in the ydj1Δ mutant strain. Ydj1 protects nascent kinases in different contexts, such as when Hsp90 is inhibited with geldanamycin or when CDC37 is mutated. The protective function of Ydj1 is due partly to its intrinsic chaperone function, but this is minor compared to the protective effect resulting from its interaction with Hsp70. SIS1, a type II Hsp40, was unable to suppress defects in kinase accumulation in the ydj1Δ mutant, suggesting some specificity in Ydj1 chaperone action. However, analysis of chimeric proteins that contained the chaperone modules of Ydj1 or Sis1 indicated that Ydj1 promotes kinase accumulation independently of its client-binding specificity. Our results suggest that Ydj1 can both protect nascent chains against degradation and control the rate of kinase maturation.