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1
Gabai, Vladimir L., and Michael Y. Sherman. "Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock." Journal of Applied Physiology 92, no. 4 (April 1, 2002): 1743–48. http://dx.doi.org/10.1152/japplphysiol.01101.2001.
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Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.
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Stope, Matthias B., Gerd Klinkmann, Karoline Diesing, Dominique Koensgen, Martin Burchardt, and Alexander Mustea. "Heat Shock Protein HSP27 Secretion by Ovarian Cancer Cells Is Linked to Intracellular Expression Levels, Occurs Independently of the Endoplasmic Reticulum Pathway and HSP27’s Phosphorylation Status, and Is Mediated by Exosome Liberation." Disease Markers 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/1575374.
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The heat shock protein HSP27 has been correlated in ovarian cancer (OC) patients with aggressiveness and chemoresistance and, therefore, represents a promising potential biomarker for OC diagnosis, prognosis, and treatment response. Notably, secretion of soluble HSP27 has been described by a few cell types and may take place as well in OC cells. Therefore, we studied HSP27 secretion mechanisms under diverse cellular conditions in an OC cell model system. Secretion of HSP27 was characterized after overexpression of HSP27 by transfected plasmids and after heat shock. Intra- and extracellular HSP27 amounts were assessed by Western blotting and ELISA. Protein secretion was blocked by brefeldin A and the impact of the HSP27 phosphorylation status was analyzed overexpressing HSP27 phosphomutants. The present study demonstrated that HSP27 secretion by OVCAR-3 and SK-OV-3 cells depends on intracellular HSP27 concentrations. Moreover, HSP27 secretion is independent of the endoplasmic reticulum secretory pathway and HSP27 phosphorylation. Notably, analysis of OC cell-born exosomes not only confirmed the concentration-dependent correlation of HSP27 expression and secretion but also demonstrated a concentration-dependent incorporation of HSP27 protein into exosomes. Thus, secreted HSP27 may become more important as an extracellular factor which controls the tumor microenvironment and might be a noninvasive biomarker.
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Winter, Julia, Elke Hammer, Jacqueline Heger, Heinz-Peter Schultheiss, Ursula Rauch, Ulf Landmesser, and Andrea Dörner. "Adenine Nucleotide Translocase 1 Expression Is Coupled to the HSP27-Mediated TLR4 Signaling in Cardiomyocytes." Cells 8, no. 12 (December 6, 2019): 1588. http://dx.doi.org/10.3390/cells8121588.
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The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.
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Singer, Debora, Can Pascal Wulff, Matthias B. Stope, and Sander Bekeschus. "Extracellular Heat Shock Protein 27 Is Released by Plasma-Treated Ovarian Cancer Cells and Affects THP-1 Monocyte Activity." Plasma 5, no. 4 (December 6, 2022): 569–78. http://dx.doi.org/10.3390/plasma5040040.
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Heat shock protein 27 (Hsp27) is a cytoprotective molecule and is inducible via oxidative stress. Anti-cancer therapies, such as the recently investigated gas plasma, subject tumor cells to a plethora of reactive oxygen species (ROS). In ovarian tumor microenvironments (TME), immune cells such as monocytes and macrophages can be found in large numbers and are often associated with cancer progression. Therefore, we quantified extracellular Hsp27 of OVCAR-3 and SK-OV-3 cells after gas plasma exposure in vitro. We found Hsp27 to be significantly increased. Following this, we investigated the effects of Hsp27 on THP-1 monocytes. Live cell imaging of Hsp27-treated THP-1 cells showed decelerated cell numbers and a reduction in cell cluster sizes. In addition, reduced metabolic activity and proliferation were identified using flow cytometry. Mitochondrial ROS production decreased. Using multicolor flow cytometry, the expression profile of eight out of twelve investigated cell surface markers was significantly modulated in Hsp27-treated THP-1 cells. A significantly decreased release of IL18 accommodated this. Taken together, our results suggest an immunomodulatory effect of Hsp27 on THP-1 monocytes. These data call for further investigations on Hsp27’s impact on the interplay of ovarian cancer cells and monocytes/macrophages under oxidative stress conditions.
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Grotegut, Pia, Sandra Kuehn, H. Burkhard Dick, and Stephanie C. Joachim. "Destructive Effect of Intravitreal Heat Shock Protein 27 Application on Retinal Ganglion Cells and Neurofilament." International Journal of Molecular Sciences 21, no. 2 (January 15, 2020): 549. http://dx.doi.org/10.3390/ijms21020549.
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Heat shock protein 27 (HSP27) is commonly involved in cellular stress. Increased levels of HSP27 as well as autoantibodies against this protein were previously detected in glaucoma patients. Moreover, systemic immunization with HSP27 induced glaucoma-like damage in rodents. Now, for the first time, the direct effects of an intravitreal HSP27 application were investigated. For this reason, HSP27 or phosphate buffered saline (PBS, controls) was applied intravitreally in rats (n = 12/group). The intraocular pressure (IOP) as well as the electroretinogram recordings were comparable in HSP27 and control eyes 21 days after the injection. However, significantly fewer retinal ganglion cells (RGCs) and amacrine cells were observed in the HSP27 group via immunohistochemistry and western blot analysis. The number of bipolar cells, on the other hand, was similar in both groups. Interestingly, a stronger neurofilament degeneration was observed in HSP27 optic nerves, while no differences were noted regarding the myelination state. In summary, intravitreal HSP27 injection led to an IOP-independent glaucoma-like damage. A degeneration of RGCs as well as their axons and amacrine cells was noted. This suggests that high levels of extracellular HSP27 could have a direct damaging effect on RGCs.
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Johnson, John D., Jay Campisi, Craig M. Sharkey, Sarah L. Kennedy, Molly Nickerson, and Monika Fleshner. "Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72." Journal of Applied Physiology 99, no. 5 (November 2005): 1789–95. http://dx.doi.org/10.1152/japplphysiol.00390.2005.
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Heat-shock protein concentrations in the blood increase after exposure to a variety of stressors, including trauma and psychological stress. Although the physiological function of extracellular heat shock protein remains controversial, there is evidence that extracellular heat shock protein 72 (Hsp72) can facilitate immunologic responses. The signal(s) that mediate(s) the in vivo elevation of extracellular Hsp72 in the blood after stressor exposure remain(s) unknown. Here we report that Hsp72 increases in the circulation via an α1-adrenergic receptor-mediated signaling pathway. Activation of α1-adrenoceptors results in a rapid increase in circulating Hsp72, and blockade of α1-adrenoceptors prevents the stress-induced rise in circulating Hsp72. Furthermore, our studies exclude a role for β-adrenoceptors, glucocorticoids, and ACTH in mediating stress-induced elevations in circulating extracellular Hsp72. Understanding the signals involved in elevating extracellular Hsp72 could facilitate the use of extracellular Hsp72 to bolster immunity and perhaps prevent exacerbation of inflammatory diseases during stress.
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Grotegut, Pia, Philipp Johannes Hoerdemann, Sabrina Reinehr, Nupur Gupta, H. Burkhard Dick, and Stephanie C. Joachim. "Heat Shock Protein 27 Injection Leads to Caspase Activation in the Visual Pathway and Retinal T-Cell Response." International Journal of Molecular Sciences 22, no. 2 (January 6, 2021): 513. http://dx.doi.org/10.3390/ijms22020513.
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Heat shock protein 27 (HSP27) is one of the small molecular chaperones and is involved in many cell mechanisms. Besides the known protective and helpful functions of intracellular HSP27, very little is known about the mode of action of extracellular HSP27. In a previous study, we showed that intravitreal injection of HSP27 led to neuronal damage in the retina and optic nerve after 21 days. However, it was not clear which degenerative signaling pathways were induced by the injection. For this reason, the pathological mechanisms of intravitreal HSP27 injection after 14 days were investigated. Histological and RT-qPCR analyses revealed an increase in endogenous HSP27 in the retina and an activation of components of the intrinsic and extrinsic apoptosis pathway. In addition, an increase in nucleus factor-kappa-light-chain-enhancer of activated B cells (NFκB), as well as of microglia/macrophages and T-cells could be observed. In the optic nerve, however, only an increased apoptosis rate was detectable. Therefore, the activation of caspases and the induction of an incipient immune response seem to be the main triggers for retinal degeneration in this intravitreal HSP27 model.
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Bitar, K. N., A. Ibitayo, and S. B. Patil. "HSP27 modulates agonist-induced association of translocated RhoA and PKC-α in muscle cells of the colon." Journal of Applied Physiology 92, no. 1 (January 1, 2002): 41–49. http://dx.doi.org/10.1152/jappl.2002.92.1.41.
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The recruitment of signal transduction molecules to the membrane is crucial for the efficient coupling of extracellular signals and contractile response. The trafficking is dynamic. We have investigated a possible cross talk between agonist-induced association of translocated RhoA and translocated protein kinase C-α (PKC-α) and a role for heat shock protein 27 (HSP27) in mediating this interaction. Immunoprecipitation with HSP27 monoclonal antibody followed by immunoblotting with either RhoA antibody or PKC-α antibody indicated that acetylcholine induced associations of HSP27-RhoA and HSP27-PKC-α in the membrane fraction but not in the cytosolic fraction. Immunoprecipitation with anti-RhoA monoclonal antibody followed by immunoblotting with PKC-α antibody indicated that acetylcholine induced a significant complexing of RhoA-PKC-α in the membrane fraction but not in the cytosolic fraction. In summary, the data indicate that agonist-induced contraction is associated with 1) association of translocated RhoA with HSP27 on the membrane, 2) association of translocated PKC-α with HSP27 on the membrane, and 3) association of PKC-α with RhoA on the membrane. The data suggest an important role for HSP27 in modulating a multiprotein complex that includes translocated RhoA and PKC-α.
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Sevin, Margaux, Nicolas Pernet, Franck Vitte, Selim Ramla, Paul Sagot, Laurent Martin, Jean Luc Villeval, et al. "HSP27: A Therapeutic Target in Myelofibrosis." Blood 128, no. 22 (December 2, 2016): 1963. http://dx.doi.org/10.1182/blood.v128.22.1963.1963.
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Abstract Myelofibrosis (MF) is the most aggressive myeloproliferative neoplasms (MPN) with the highest degree of morbidity and mortality, including progressive bone marrow fibrosis resulting into bone marrow failure. JAK2 kinase inhibitors have been successfully used for a few years in MPN and more particularly for MF treatment. Despite their beneficial effects on spleen size and symptoms, JAK2 inhibitors induce low molecular and survival responses underscoring the urgent need for other therapeutic approaches. Recently, heat shock protein 90 (HSP90) - known to stabilize JAK2 - has been reported as a promising therapeutic target in MPN. However HSP90 inhibitors show toxicity and induce the expression of stress-inducible proteins like HSP70 and, most likely HSP27 as previously shown in other cancers. In addition, we and others have shown that HSP27, was strongly expressed in patients with idiopathic pulmonary, lung or kidney tubulointerstitial fibrosis, underlying a relevant role of HSP27 in fibrotic processes. Taking into account both the beneficial effects of HSP inhibitors in leukemia and in MPN, and the possible implication of HSP27 in fibrosis, we have evaluated in this work, the status of HSP27 in MF patient's samples and assess the effectiveness of an HSP27 oligonucleotide inhibitor called OGX-427. In this study, we first assessed the extracellular and intracellular level of HSPs from MF patients by ELISA, flow cytometry and by immunohistochemistry. We observed for the first time a specific increase in both intracellular and extracellular HSP27 in CD34+ circulating hematopoietic progenitor cells (n=9-16; P=0.0097) and in the sera of patients (n=24-27; P<0.0001) with MF compared with healthy donors, respectively. Moreover, we identified the presence of HSP27 in the bone marrow's MF patients. We then investigated the in vivo impact of OGX-427, a specific inhibitor of HSP27, or an oligonucleotide control in a murine TPO-induced MF mouse model. The use of OGX-427 limited the progression of the disease in our MF mouse model (n=9). In particular, OGX-427 was associated with a marked reduction in both the spleen weight and size. Also, we noted a decrease of megakaryocyte hyperplasia in the bone marrow accompanied by a visible restoration of spleen structure and lymphoid white pulp territories with OGX-427. Taking altogether, our results support a key role of HSP27 in the pathophysiology in MF and highlight the potential therapeutic benefit of HSP27 inhibitors in this disorder. Disclosures No relevant conflicts of interest to declare.
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Hatakeyama, Daijiro, Osamu Kozawa, Masayuki Niwa, Hiroyuki Matsuno, Kanefusa Kato, Norichika Tatematsu, Toshiyuki Shibata, and Toshihiko Uematsu. "Inhibition by adenylyl cyclase-cAMP system of ET-1-induced HSP27 in osteoblasts." American Journal of Physiology-Endocrinology and Metabolism 281, no. 6 (December 1, 2001): E1260—E1266. http://dx.doi.org/10.1152/ajpendo.2001.281.6.e1260.
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We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12- O-tetradecanoylphorbol-13-acetate (TPA). PGE1, an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE1. Forskolin, DBcAMP, and PGE1suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.
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Arslan, Badel, Nurcan Aras, Selma Yaman, and Ulku Comelekoglu. "Investigation of genetic stress parameters in brain tissues of rats exposed to 1.8 GHz cell phone radiofrequency electromagnetic field." Medicine Science | International Medical Journal 13, no. 1 (2024): 78. http://dx.doi.org/10.5455/medscience.2023.06.094.
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Heat Shock Proteins (HSPs) may induce various cellular processes, including replication, apoptosis, cell-cycle progression. Mitogen-activated protein kinase (MAPK) cascades are the primary mechanism that mediates the cellular stress response to extracellular stimuli and regulates transcriptional activity. It has been shown that mobile phone exposure can stimulate the Hsp27/p38MAPK stress pathway. In this study, twenty-seven mature female Wistar albino rats were exposed to 1.8 GHz radiofrequency electromagnetic field (RF-EMF) 2h/day for 8 weeks (SAR: 0.06 W/kg). Hsp27 and p38MAPK gene expressions were investigated in rat brains. Rats were divided into groups sham-exposed, cage control, and 1.8 GHz RF-EMF exposed. Hsp27 and p38MAPK gene expression levels were investigated from the brain. p38MAPK expression was found to be upregulated in RF-EMF exposed group (p=0.018) Hsp27 expressions were not altered (p=0.897). In conclusion, long-term exposure to 1.8 GHz cell phone radiation can activate the Hsp27/p38MAPK stress pathway. It may cause several cellular disorders and can affect brain function.
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Shi, Chunhua, Daiana Alvarez-Olmedo, Yuan Zhang, Badal S. B. Pattar, and Edward R. O’Brien. "The Heat Shock Protein 27 Immune Complex Enhances Exosomal Cholesterol Efflux." Biomedicines 8, no. 8 (August 17, 2020): 290. http://dx.doi.org/10.3390/biomedicines8080290.
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Previously, we demonstrated that Heat Shock Protein 27 (HSP27) reduces the inflammatory stages of experimental atherogenesis, is released by macrophage (MΦ) exosomes and lowers cholesterol levels in atherosclerotic plaques. Recently, we discovered that natural autoantibodies directed against HSP27 enhance its signaling effects, as HSP27 immune complexes (IC) interact at the cell membrane to modulate signaling. We now seek to evaluate the potential role of the HSP27 IC on MΦ exosomal release and cholesterol export. First, in human blood samples, we show that healthy control subjects have 86% more exosomes compared to patients with coronary artery disease (p < 0.0001). Treating human THP-1 MΦ with rHSP27 plus a validated anti-HPS27 IgG antibody increased the abundance of exosomes in the culture media (+98%; p < 0.0001) as well as expression of Flotillin-2, a marker reflective of exosomal release. Exosome cholesterol efflux was independent of Apo-A1. THP-1 MΦ loaded with NBD-labeled cholesterol and treated with the HSP27 IC showed a 22% increase in extracellular vesicles labeled with NBD and a 95% increase in mean fluorescent intensity. In conclusion, exosomal abundance and secretion of cholesterol content increases in response to HSP27 IC treatment, which may represent an important therapeutic option for diseases characterized by cholesterol accumulation.
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Singer, Debora, Verena Ressel, Matthias B. Stope, and Sander Bekeschus. "Heat Shock Protein 27 Affects Myeloid Cell Activation and Interaction with Prostate Cancer Cells." Biomedicines 10, no. 9 (September 5, 2022): 2192. http://dx.doi.org/10.3390/biomedicines10092192.
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Heat shock proteins are cytoprotective molecules induced by environmental stresses. The small heat shock protein 27 (Hsp27) is highly expressed under oxidative stress conditions, mediating anti-oxidative effects and blocking apoptosis. Since medical gas plasma treatment subjects cancer cells to a multitude of reactive oxygen species (ROS), inducing apoptosis and immunomodulation, probable effects of Hsp27 should be investigated. To this end, we quantified the extracellular Hsp27 in two prostate cancer cell lines (LNCaP, PC-3) after gas plasma-induced oxidative stress, showing a significantly enhanced release. To investigate immunomodulatory effects, two myeloid cell lines (THP-1 and HL-60) were also exposed to Hsp27. Only negligible effects on viability, intracellular oxidative milieu, and secretion profiles of the myeloid cells were found when cultured alone. Interestingly, prostate cancer-myeloid cell co-cultures showed altered secretion profiles with a significant decrease in vascular endothelial growth factor (VEGF) release. Furthermore, the myeloid surface marker profiles were changed, indicating an enhanced differentiation in co-culture upon Hsp27 treatment. Finally, we investigated morphological changes, proliferation, and interaction with prostate cancer cells, and found significant alterations in the myeloid cells, supporting the tendency to differentiate. Collectively, our results suggest an ambiguous effect of Hsp27 on myeloid cells in the presence of prostate cancer cells which needs to be further investigated.
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Yamboliev, Ilia A., Jason C. Hedges, Jack L. M. Mutnick, Leonard P. Adam, and William T. Gerthoffer. "Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 6 (June 1, 2000): H1899—H1907. http://dx.doi.org/10.1152/ajpheart.2000.278.6.h1899.
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Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.
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Musiał, Kinga, and Danuta Zwolińska. "Extracellular Hsp27 in patients with chronic kidney disease." Kidney International 83, no. 5 (May 2013): 971. http://dx.doi.org/10.1038/ki.2013.33.
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Hyväri, Laura, Sari Vanhatupa, Miina Ojansivu, Minna Kelloniemi, Toni-Karri Pakarinen, Leena Hupa, and Susanna Miettinen. "Heat Shock Protein 27 Is Involved in the Bioactive Glass Induced Osteogenic Response of Human Mesenchymal Stem Cells." Cells 12, no. 2 (January 5, 2023): 224. http://dx.doi.org/10.3390/cells12020224.
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Bioactive glass (BaG) materials are increasingly used in clinics, but their regulatory mechanisms on osteogenic differentiation remain understudied. In this study, we elucidated the currently unknown role of the p38 MAPK downstream target heat shock protein 27 (HSP27), in the osteogenic commitment of human mesenchymal stem cells (hMSCs), derived from adipose tissue (hASCs) and bone marrow (hBMSCs). Osteogenesis was induced with ionic extract of an experimental BaG in osteogenic medium (OM). Our results showed that BaG OM induced fast osteogenesis of hASCs and hBMSCs, demonstrated by enhanced alkaline phosphatase (ALP) activity, production of extracellular matrix protein collagen type I, and matrix mineralization. BaG OM stimulated early and transient activation of p38/HSP27 signaling by phosphorylation in hMSCs. Inhibition of HSP27 phosphorylation with SB202190 reduced the ALP activity, mineralization, and collagen type I production induced by BaG OM. Furthermore, the reduced pHSP27 protein by SB202190 corresponded to a reduced F-actin intensity of hMSCs. The phosphorylation of HSP27 allowed its co-localization with the cytoskeleton. In terminally differentiated cells, however, pHSP27 was found diffusely in the cytoplasm. This study provides the first evidence that HSP27 is involved in hMSC osteogenesis induced with the ionic dissolution products of BaG. Our results indicate that HSP27 phosphorylation plays a role in the osteogenic commitment of hMSCs, possibly through the interaction with the cytoskeleton.
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Guay, J., H. Lambert, G. Gingras-Breton, J. N. Lavoie, J. Huot, and J. Landry. "Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27." Journal of Cell Science 110, no. 3 (February 1, 1997): 357–68. http://dx.doi.org/10.1242/jcs.110.3.357.
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We have studied the contribution of the individual kinases of the MAP (mitogen-activated protein) kinase family, including ERK (extracellular-signal regulated kinase), JNK/SAPK (c-JUN NH2-terminal kinase/stress-activated protein kinase) and p38, to activation of the HSP27 (heat shock protein 27) kinase MAPKAP kinase-2/3 and to HSP27 phosphorylation in Chinese hamster CCL39 cells stimulated by either growth factors, cytokines or stressing agents. In vitro assays using fractionated cell extracts or immunoprecipitates indicated that only fractions containing ERK or p38, and not those containing JNK/SAPK, had the capacity to activate MAPKAP kinase-2/3. In vivo, however, it appeared that only p38 is an upstream activator of HSP27 phosphorylation after both stress or growth factor stimulation: expression of an interfering mutant of ras, which blocked the activation of ERK by both types of inducers, had no effect on HSP27 phosphorylation and p38 activation; and the cell-permeant specific inhibitor of 038, SB203580, blocked MAPKAP-kinase2/3 activation and HSP27 phosphorylation. HSP27 has been suggested to have a phosphorylation-activated homeostatic function at the actin cytoskeleton level. This raises the possibility that p38 might be directly involved in mediating actin responses to external stimuli. Accordingly, we observed that a prior activation of p38 increased the stability of the actin microfilaments in cells exposed to cytochalasin D. The effect was dependent on the expression of HSP27 and was totally annihilated by blocking the p38 activity with SB203580. The results provide strong support to the idea that activation of p38 during adverse environmental conditions serves a homeostatic function aimed at regulating actin dynamics that would otherwise be destabilized during stress. Its activation during normal agonist stimulation may constitute an additional actin signaling pathway, the importance of which depends on the level of expression of HSP27.
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Ishida, Yoshihito, Hiroshi Kubota, Akitsugu Yamamoto, Akira Kitamura, Hans Peter Bächinger, and Kazuhiro Nagata. "Type I Collagen in Hsp47-null Cells Is Aggregated in Endoplasmic Reticulum and Deficient in N-Propeptide Processing and Fibrillogenesis." Molecular Biology of the Cell 17, no. 5 (May 2006): 2346–55. http://dx.doi.org/10.1091/mbc.e05-11-1065.
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Heat-shock protein of 47 kDa (Hsp47) is a molecular chaperone that recognizes collagen triple helices in the endoplasmic reticulum (ER). Hsp47-knockout mouse embryos are deficient in the maturation of collagen types I and IV, and collagen triple helices formed in the absence of Hsp47 show increased susceptibility to protease digestion. We show here that the fibrils of type I collagen produced by Hsp47-/- cells are abnormally thin and frequently branched. Type I collagen was highly accumulated in the ER of Hsp47-/- cells, and its secretion rate was much slower than that of Hsp47+/+ cells, leading to accumulation of the insoluble aggregate of type I collagen within the cells. Transient expression of Hsp47 in the Hsp47-/- cells restored normal extracellular fibril formation and intracellular localization of type I collagen. Intriguingly, type I collagen with unprocessed N-terminal propeptide (N-propeptide) was secreted from Hsp47-/- cells and accumulated in the extracellular matrix. These results indicate that Hsp47 is required for correct folding and prevention of aggregation of type I collagen in the ER and that this function is indispensable for efficient secretion, processing, and fibril formation of collagen.
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Thuringer, Dominique, Gaetan Jego, Guillaume Wettstein, Olivier Terrier, Laurent Cronier, Nadhir Yousfi, Sophie Hébrard, et al. "Extracellular HSP27 mediates angiogenesis through Toll‐like receptor 3." FASEB Journal 27, no. 10 (June 26, 2013): 4169–83. http://dx.doi.org/10.1096/fj.12-226977.
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Osorio, Luis A., Mauricio Lozano, Paola Soto, Viviana Moreno-Hidalgo, Angely Arévalo-Gil, Angie Ramírez-Balaguera, Daniel Hevia, et al. "Levels of Small Extracellular Vesicles Containing hERG-1 and Hsp47 as Potential Biomarkers for Cardiovascular Diseases." International Journal of Molecular Sciences 25, no. 9 (April 30, 2024): 4913. http://dx.doi.org/10.3390/ijms25094913.
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The diagnosis of cardiovascular disease (CVD) is still limited. Therefore, this study demonstrates the presence of human ether-a-go-go-related gene 1 (hERG1) and heat shock protein 47 (Hsp47) on the surface of small extracellular vesicles (sEVs) in human peripheral blood and their association with CVD. In this research, 20 individuals with heart failure and 26 participants subjected to cardiac stress tests were enrolled. The associations between hERG1 and/or Hsp47 in sEVs and CVD were established using Western blot, flow cytometry, electron microscopy, ELISA, and nanoparticle tracking analysis. The results show that hERG1 and Hsp47 were present in sEV membranes, extravesicularly exposing the sequences 430AFLLKETEEGPPATE445 for hERG1 and 169ALQSINEWAAQTT- DGKLPEVTKDVERTD196 for Hsp47. In addition, upon exposure to hypoxia, rat primary cardiomyocytes released sEVs into the media, and human cardiomyocytes in culture also released sEVs containing hERG1 (EV-hERG1) and/or Hsp47 (EV-Hsp47). Moreover, the levels of sEVs increased in the blood when cardiac ischemia was induced during the stress test, as well as the concentrations of EV-hERG1 and EV-Hsp47. Additionally, the plasma levels of EV-hERG1 and EV-Hsp47 decreased in patients with decompensated heart failure (DHF). Our data provide the first evidence that hERG1 and Hsp47 are present in the membranes of sEVs derived from the human cardiomyocyte cell line, and also in those isolated from human peripheral blood. Total sEVs, EV-hERG1, and EV-Hsp47 may be explored as biomarkers for heart diseases such as heart failure and cardiac ischemia.
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Huot, Jacques, François Houle, Simon Rousseau, Réna G. Deschesnes, Girish M. Shah, and Jacques Landry. "SAPK2/p38-dependent F-Actin Reorganization Regulates Early Membrane Blebbing during Stress-induced Apoptosis." Journal of Cell Biology 143, no. 5 (November 30, 1998): 1361–73. http://dx.doi.org/10.1083/jcb.143.5.1361.
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In endothelial cells, H2O2 induces the rapid formation of focal adhesion complexes at the ventral face of the cells and a major reorganization of the actin cytoskeleton into dense transcytoplasmic stress fibers. This change in actin dynamics results from the activation of the mitogen-activated protein (MAP) kinase stress-activated protein kinase-2/p38 (SAPK2/p38), which, via MAP kinase-activated protein (MAPKAP) kinase-2/3, leads to the phosphorylation of the actin polymerization modulator heat shock protein of 27 kD (HSP27). Here we show that the concomitant activation of the extracellular signal-regulated kinase (ERK) MAP kinase pathway by H2O2 accomplishes an essential survival function during this process. When the activation of ERK was blocked with PD098059, the focal adhesion complexes formed under the plasma membrane, and the actin polymerization activity led to a rapid and intense membrane blebbing. The blebs were delimited by a thin F-actin ring and contained enhanced levels of HSP27. Later, the cells displayed hallmarks of apoptosis, such as DEVD protease activities and internucleosomal DNA fragmentation. Bleb formation but not apoptosis was blocked by extremely low concentrations of the actin polymerization inhibitor cytochalasin D or by the SAPK2 inhibitor SB203580, indicating that the two processes are not in the same linear cascade. The role of HSP27 in mediating membrane blebbing was assessed in fibroblastic cells. In control fibroblasts expressing a low level of endogenous HSP27 or in fibroblasts expressing a high level of a nonphosphorylatable HSP27, H2O2 did not induce F-actin accumulation, nor did it generate membrane blebbing activity in the presence or absence of PD098059. In contrast, in fibroblasts that expressed wild-type HSP27 to a level similar to that found in endothelial cells, H2O2 induced accumulation of F-actin and caused bleb formation when the ERK pathway was inhibited. Cis-platinum, which activated SAPK2 but induced little ERK activity, also induced membrane blebbing that was dependent on the expression of HSP27. In these cells, membrane blebbing was not followed by caspase activation or DNA fragmentation. We conclude that the HSP27-dependent actin polymerization–generating activity of SAPK2 associated with a misassembly of the focal adhesions is responsible for induction of membrane blebbing by stressing agents.
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Asea, Alexzander. "Initiation of the Immune Response by Extracellular Hsp72: Chaperokine Activity of Hsp72." Current Immunology Reviews 2, no. 3 (August 1, 2006): 209–15. http://dx.doi.org/10.2174/157339506778018514.
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Yamada, Paulette M., Fabiano T. Amorim, Pope Moseley, Robert Robergs, and Suzanne M. Schneider. "Effect of heat acclimation on heat shock protein 72 and interleukin-10 in humans." Journal of Applied Physiology 103, no. 4 (October 2007): 1196–204. http://dx.doi.org/10.1152/japplphysiol.00242.2007.
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Heat acclimation (HA) results in whole body adaptations that increase heat tolerance, and in addition, HA may also result in protective cellular adaptations. We hypothesized that, after HA, basal intracellular heat shock protein (HSP) 72 and extracellular IL-10 levels would increase, while extracellular HSP72 levels decrease. Ten male and two female subjects completed a 10-day exercise/HA protocol (100-min exercise bout at 56% of maximum O2 uptake in a 42.5°C DB, 27.9% RH environment); subjects exhibited classic adaptations that accompany HA. Peripheral blood mononuclear cells (PBMCs) were isolated before and after each acclimation session on days 1, 6, and 10; plasma and serum were collected before and after exercise on the 1st and 10th day of HA. SDS-PAGE was used to determine PBMC HSP72 levels during HA, and ELISA was used to measure plasma IL-10 and serum HSP72 concentrations. The increase in PBMC HSP72 from pre- to postexercise on the 1st day of HA was not significant (mean ± SD, 1.0 ± 0 vs. 1.6 ± 0.6 density units). Preexercise HSP72 levels on day 1 were significantly lower compared with the pre- and postexercise samples on days 6 and 10 (mean ± SD, day 6: 2.1 ± 1.0 and 2.2 ± 1.0, day 10: 2.0 ± 1.3 and 2.2 ± 1.0 density units, respectively, P < 0.05). There were no differences in plasma IL-10 and serum HSP72 postexercise or after 10 days of HA. The sustained elevation of HSP72 from days 6 to 10 may be evidence of a cellular adaptation to HA that contributes to improved heat tolerance and reduced heat illness risk.
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Ganter, Michael T., Lorraine B. Ware, Marybeth Howard, Jérémie Roux, Brandi Gartland, Michael A. Matthay, Monika Fleshner, and Jean-François Pittet. "Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 3 (September 2006): L354—L361. http://dx.doi.org/10.1152/ajplung.00405.2005.
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Previous studies have shown that heat shock protein 72 (Hsp72) is found in the extracellular space (eHsp72) and that eHsp72 has potent immunomodulatory effects. However, whether eHsp72 is present in the distal air spaces and whether eHsp72 could modulate removal of alveolar edema is unknown. The first objective was to determine whether Hsp72 is released within air spaces and whether Hsp72 levels in pulmonary edema fluid would correlate with the capacity of the alveolar epithelium to remove alveolar edema fluid in patients with ALI/ARDS. Patients with hydrostatic edema served as controls. The second objective was to determine whether activation of the stress protein response (SPR) caused the release of Hsp72 into the extracellular space in vivo and in vitro and to determine whether SPR activation and/or eHsp72 itself would prevent the IL-1β-mediated inhibition of the vectorial fluid transport across alveolar type II cells. We found that eHsp72 was present in plasma and pulmonary edema fluid of ALI patients and that eHsp72 was significantly higher in pulmonary edema fluid from patients with preserved alveolar epithelial fluid clearance. Furthermore, SPR activation in vivo in mice and in vitro in lung endothelial, epithelial, and macrophage cells caused intracellular expression and extracellular release of Hsp72. Finally, SPR activation, but not eHsp72 itself, prevented the decrease in alveolar epithelial ion transport induced by exposure to IL-1β. Thus SPR may protect the alveolar epithelium against oxidative stress associated with experimental ALI, and eHsp72 may serve as a marker of SPR activation in the distal air spaces of patients with ALI.
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Xiong, Gaofeng, Jie Chen, Guoying Zhang, Shike Wang, Kunito Kawasaki, Jieqing Zhu, Yan Zhang, et al. "Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction." Proceedings of the National Academy of Sciences 117, no. 7 (February 3, 2020): 3748–58. http://dx.doi.org/10.1073/pnas.1911951117.
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Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs.
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Beck, Franz-X., Wolfgang Neuhofer, and Eva Müller. "Molecular chaperones in the kidney: distribution, putative roles, and regulation." American Journal of Physiology-Renal Physiology 279, no. 2 (August 1, 2000): F203—F215. http://dx.doi.org/10.1152/ajprenal.2000.279.2.f203.
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Molecular chaperones are intracellular proteins that prevent inappropriate intra- and intermolecular interactions of polypetide chains. A specific group of highly conserved molecular chaperones are the heat shock proteins (HSPs), many of which are constitutively expressed but most of which are inducible by diverse (in some cases specific) stress factors. HSPs, either alone or in cooperation with “partner” chaperones, are involved in cellular processes as disparate as correct folding and assembly of proteins, transport of proteins to specific intracellular locations, protein degradation, and preservation and restructuring of the cytoskeleton. The characteristic distribution of individual HSPs in the kidney, and their response to different challenges, suggests that a number of HSPs may fulfill specific, kidney-related functions. HSP72 and the osmotic stress protein 94 (Osp94) appear to participate in the adaptation of medullary cells to high extracellular salt and urea concentrations; the small HSPs (HSP25/27 and crystallins) may be involved in the function of mesangial cells and podocytes and contribute to the volume-regulatory remodeling of the cytoskeleton in medullary cells during changes in extracellular tonicity. HSP90 contributes critically to the maturation of steroid hormone receptors and may thus be a critical determinant of the aldosterone sensitivity of specific renal epithelial cells. Certain HSPs are also induced in various pathological states of the kidney. The observation that the expression of individual HSPs in specific kidney diseases often displays characteristic time courses and intrarenal distribution patterns supports the idea that HSPs are involved in the recovery but possibly also in the initiation and/or maintenance phases of these disturbances.
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Gabai, Vladimir L., Julia A. Yaglom, Todd Waldman, and Michael Y. Sherman. "Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells." Molecular and Cellular Biology 29, no. 2 (November 10, 2008): 559–69. http://dx.doi.org/10.1128/mcb.01041-08.
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ABSTRACT The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its levels often correlate with poor prognosis. Previously we reported that knockdown of Hsp72 in certain cancer cells, but not in untransformed breast epithelial cells, triggers senescence via p53-dependent and p53-independent mechanisms. Here we demonstrate that the p53-dependent pathway controlled by Hsp72 depends on the oncogenic form of phosphatidylinositol 3-kinase (PI3K). Indeed, upon expression of the oncogenic PI3K, epithelial cells began responding to Hsp72 depletion by activating the p53 pathway. Moreover, in cancer cell lines, activation of the p53 pathway caused by depletion of Hsp72 was dependent on oncogenes that activate the PI3K pathway. On the other hand, the p53-independent senescence pathway controlled by Hsp72 was associated with the Ras oncogene. In this pathway, extracellular signal-regulated kinases (ERKs) were critical for senescence, and Hsp72 controlled the ERK-activating kinase cascade at the level of Raf-1. Importantly, upon Ras expression, untransformed cells started responding to knockdown of Hsp72 by constitutive activation of ERKs, culminating in senescence. Therefore, Hsp72 is intimately involved in suppression of at least two separate senescence signaling pathways that are regulated by distinct oncogenes in transformed cells, which explains why cancer cells become “addicted” to this heat shock protein.
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Edwards, Helen V., John D. Scott, and George S. Baillie. "The A-kinase-anchoring protein AKAP-Lbc facilitates cardioprotective PKA phosphorylation of Hsp20 on Ser16." Biochemical Journal 446, no. 3 (August 28, 2012): 437–43. http://dx.doi.org/10.1042/bj20120570.
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Hsp20 (heat-shock protein of 20 kDa; HspB6) is a cardioprotective agent which combats a number of pathophysiological processes in the heart, including hypertrophy, apoptosis and ischaemia/reperfusion injury. The cardioprotective actions of Hsp20 require its phosphorylation by PKA (cAMP-dependent protein kinase) on Ser16. Although the extracellular stimuli that promote cAMP-responsive phosphorylation of Hsp20 are well known, less is understood about the molecular processes that regulate this modification. AKAPs (A-kinase-anchoring proteins) physically compartmentalize PKA to specific locations within a cell to both direct PKA phosphorylation toward selected substrates and to orchestrate downstream signalling events. In the present study we used PKA anchoring disruptor peptides to verify that an AKAP underpins the cardioprotective phosphorylation of Hsp20. Biochemical and immunofluorescence techniques identify the cytosolic protein AKAP-Lbc (AKAP13) as the anchoring protein responsible for directing PKA phosphorylation of Hsp20 on Ser16. Gene silencing and rescue experiments establish that AKAP-Lbc-mediated PKA phosphorylation of Hsp20 is crucial to the anti-apoptotic effects of the Hsp. Thus AKAP-Lbc may serve an ancillary cardioprotective role by favouring the association of PKA with Hsp20.
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Xue, Jing, Jie Zhou, and Janos Zempleni. "Holocarboxylase synthetase catalyzes biotinylation of heat shock protein 72, thereby inducing RANTES expression in HEK-293 cells." American Journal of Physiology-Cell Physiology 305, no. 12 (December 15, 2013): C1240—C1245. http://dx.doi.org/10.1152/ajpcell.00279.2013.
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In a recent mass spectrometry screen, we identified 108 new proteins that were modified endogenously by covalent binding of biotin; members of the heat shock superfamily of proteins, including heat shock protein 72 (HSP72), were overrepresented among the biotinylated proteins. Mammals respond to infections by secreting extracellular HSP72 (eHSP72), which elicits an immune response. Here, using mass spectrometry and site-directed mutagenesis, we identified five biotinylation sites in HSP72. We used coimmunoprecipitation, mass spectrometry, and limited proteolysis assays to demonstrate that HSP72 interacts physically with the protein biotin ligase holocarboxylase synthetase (HLCS), leading to biotinylation of residues K112, K128 K348, K361, K415, and, probably, additional lysines. Finally, we demonstrated that HLCS-dependent biotinylation of eHSP72 increases expression of the chemokine regulated on activation normal T-expressed and presumably secreted (RANTES) by human embryonic kidney (HEK-293) cells. In conclusion, we report a novel endogenous modification of HSP72 and demonstrated that binding of biotin to eHSP72 prepares cells for a strong immune response.
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Bigham, Michael T., and Hector R. Wong. "THE ROLE OF EXTRACELLULAR HSP72 IN CARDIOMYOCYTE ACTIVATION." Critical Care Medicine 34 (December 2006): A44. http://dx.doi.org/10.1097/00003246-200612002-00153.
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Lee, W. C., H. C. Wen, C. P. Chang, M. Y. Chen, and M. T. Lin. "Heat shock protein 72 overexpression protects against hyperthermia, circulatory shock, and cerebral ischemia during heatstroke." Journal of Applied Physiology 100, no. 6 (June 2006): 2073–82. http://dx.doi.org/10.1152/japplphysiol.01433.2005.
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This study extends our earlier studies in rats by applying our heatstroke model to a new species. Additionally, transgenic mice are used to examine the role of heat shock protein (HSP) 72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70i gene ([+]HSP72), transgene-negative littermate controls ([−]HSP72), and normal Institute of Cancer Research strain mice (ICR) under pentobarbital sodium anesthesia were subjected to heat stress (40°C) to induce heatstroke. In [−]HSP72 or ICR, the values for mean arterial pressure, the striatal blood flow, and the striatal Po2 after the onset of heatstroke were significantly lower than those in preheat controls. The core and brain temperatures, the extracellular concentrations of ischemic and injury markers in the striatum, and the striatal neuronal damage scores were significantly greater than those in the preheat controls. In [−]HSP72 or ICR, the body temperatures, cell ischemia content, and injury marker in the striatum were significantly higher, and the mean arterial pressure, striatal blood flow, and striatal Po2 concentration were significantly lower during heatstroke than in [+]HSP72. Accordingly, the latency and the survival times for [+]HSP72 significantly exceeded those of [−]HSP72 or ICR. These results demonstrate that the overexpression of HSP72 in multiple organs improves survival during heatstroke by reducing hyperthermia, circulatory shock, and cerebral ischemia and damage in mice.
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Neuhofer, Wolfgang, Karin Lugmayr, Maria-Luisa Fraek, and Franz-X. Beck. "Regulated Overexpression of Heat Shock Protein 72 Protects Madin-Darby Canine Kidney Cells from the Detrimental Effects of High Urea Concentrations." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2565–71. http://dx.doi.org/10.1681/asn.v12122565.
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ABSTRACT. Exposure of renal medullary cells to elevated extracellular NaCl concentrations is associated with increased heat shock protein 72 (HSP72) expression and improved resistance to subsequent exposure to a high urea concentration (600 mM). To establish a causal relationship between HSP72 expression and protection against high urea concentrations, HSP72 was inducibly overexpressed in Madin-Darby canine kidney (MDCK) cells, in the absence of hypertonic stress before urea exposure. For this purpose, the human stress-inducible HSP72 gene was cloned downstream from a dexamethasone (DEX)-inducible promoter in the eukaryotic expression vector pLKneo. This construct allowed robust induction of HSP72 by exposure of stably transfected MDCK cells (MDCK-LK72) to 0.1 μM DEX. Increased HSP72 abundance significantly improved survival rates after 24-h exposure of the cells to medium containing 600 mM urea (14 versus 43%). In mock-transfected or wild-type cells, DEX had no significant effect on HSP72 abundance or urea resistance. In accordance with those findings, lactate dehydrogenase activity in the supernatant was significantly reduced, compared with appropriate control samples, only in MDCK-LK72 cells overexpressing HSP72. Labeling with annexin V-FITC and propidium iodide, followed by flow cytometry, revealed that overexpression of HSP72 was associated with a reduction in the number of apoptotic-lysed cells, a concomitant retardation of apoptosis, and an increase in the number of viable cells. These data support the view that HSP72, which is very abundant in the renal inner medulla, is an important component of the defense mechanism of medullary cells against extreme concentrations of urea.
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Xiao, Hong-bo, Rui-hong Liu, Guang-hui Ling, Li Xiao, Yuan-chen Xia, Fu-you Liu, Jun Li, et al. "HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1 through ERK1/2 and JNK MAPK pathways." American Journal of Physiology-Renal Physiology 303, no. 5 (September 1, 2012): F757—F765. http://dx.doi.org/10.1152/ajprenal.00470.2011.
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Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-β1-induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF-β1 would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.
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Kim, Sung O., Christopher P. Baines, Stuart D. Critz, Steven L. Pelech, Sidney Katz, James M. Downey, and Michael V. Cohen. "Ischemia induced activation of heat shock protein 27 kinases and casein kinase 2 in the preconditioned rabbit heart." Biochemistry and Cell Biology 77, no. 6 (December 1, 1999): 559–67. http://dx.doi.org/10.1139/o99-065.
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Protein kinase C (PKC), p38 MAP kinase, and mitogen-activated protein kinase-activated kinases 2 and 3 (MAPKAPK2 and MAPKAPK3) have been implicated in ischemic preconditioning (PC) of the heart to reduce damage following a myocardial infarct. This study examined whether extracellular signal-regulated kinase (Erk) 1, p70 ribosomal S6 kinase (p70 S6K), casein kinase 2 (CK2), and other hsp27 kinases are also activated by PC, and if they are required for protection in rabbit hearts. CK2 and hsp27 kinase activities declined during global ischemia in control hearts, whereas PC with 5 min ischemia and 10 min reperfusion increased their activities during global ischemia. Resource Q chromatography resolved two distinct peaks of hsp27 phosphotransferase activities; the first peak (at 0.36 M NaCl) appeared to correspond to the 55-kDa MAPKAPK2. Erk1 activity was elevated in both control and PC hearts after post-ischemic reperfusion, but no change was observed in p70 S6K activity. Infarct size (measured by triphenyltetrazolium staining) in isolated rabbit hearts subjected to 30 min regional ischemia and 2 h reperfusion was 31.0 ± 2.6% of the risk zone in controls and was 10.3 ± 2.2% in PC hearts (p < 0.001). Neither the CK2 inhibitor 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) nor the Mek1/2 inhibitor PD98059 infused during ischemia blocked protection by PC. The activation of CK2 and Erk1 in ischemic preconditioned hearts appear to be epiphenomena and not required for the reduction of infarction from myocardial ischemia.Key words: Erk1, MAPKAPK2, PD98059, p38 MAPK.
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Sakamoto, Noriho, Daisuke Okuno, Takatomo Tokito, Hirokazu Yura, Takashi Kido, Hiroshi Ishimoto, Yoshimasa Tanaka, and Hiroshi Mukae. "HSP47: A Therapeutic Target in Pulmonary Fibrosis." Biomedicines 11, no. 9 (August 25, 2023): 2387. http://dx.doi.org/10.3390/biomedicines11092387.
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Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by a progressive decline in lung function and poor prognosis. The deposition of the extracellular matrix (ECM) by myofibroblasts contributes to the stiffening of lung tissue and impaired oxygen exchange in IPF. Type I collagen is the major ECM component and predominant collagen protein deposited in chronic fibrosis, suggesting that type I collagen could be a target of drugs for fibrosis treatment. Heat shock protein 47 (HSP47), encoded by the serpin peptidase inhibitor clade H, member 1 gene, is a stress-inducible collagen-binding protein. It is an endoplasmic reticulum-resident molecular chaperone essential for the correct folding of procollagen. HSP47 expression is increased in cellular and animal models of pulmonary fibrosis and correlates with pathological manifestations in human interstitial lung diseases. Various factors affect HSP47 expression directly or indirectly in pulmonary fibrosis models. Overall, understanding the relationship between HSP47 expression and pulmonary fibrosis may contribute to the development of novel therapeutic strategies.
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Bruchim, Yaron, Itamar Aroch, Ady Eliav, Atallah Abbas, Ilan Frank, Efrat Kelmer, Carolina Codner, Gilad Segev, Yoram Epstein, and Michal Horowitz. "Two years of combined high-intensity physical training and heat acclimatization affect lymphocyte and serum HSP70 in purebred military working dogs." Journal of Applied Physiology 117, no. 2 (July 15, 2014): 112–18. http://dx.doi.org/10.1152/japplphysiol.00090.2014.
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Military working dogs in hot countries undergo exercise training at high ambient temperatures for at least 9 mo annually. Physiological adaptations to these harsh conditions have been extensively studied; however, studies focusing on the underlying molecular adaptations are limited. In the current study, military working dogs were chosen as a model to examine the effects of superimposing endurance exercise on seasonal acclimatization to environmental heat stress. The lymphocyte HSP70 profile and extracellular HSP70 were studied in tandem with physiological performance in the dogs from their recruitment for the following 2 yr. Aerobic power and heat shock proteins were measured at the end of each summer, with physical performance tests (PPTs) in an acclimatized room (22°C). The study shows that together with a profound enhancement of aerobic power and physical performance, hsp72 mRNA induction immediately post-PPT and 45 min later, progressively increased throughout the study period (relative change in median lymphocyte hsp72 mRNA first PPT, 4.22 and 12.82; second PPT, 17.19 and 109.05, respectively), whereas induction of HSP72 protein was stable. These responses suggest that cellular/molecular adaptive tools for maintaining HSP72 homeostasis exist. There was also a significant rise in basal and peak median optical density extracellular HSP at the end of each exercise test (first PPT, 0.13 and 0.15; second PPT, 1.04 and 1.52, respectively). The relationship between these enhancements and improved aerobic power capacity is not yet fully understood.
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Vallés, Gema, Eduardo García-Cimbrelo, and Nuria Vilaboa. "Involvement of extracellular Hsp72 in wear particle-mediated osteolysis." Acta Biomaterialia 8, no. 3 (March 2012): 1146–55. http://dx.doi.org/10.1016/j.actbio.2011.12.001.
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Salari, Samira, Tara Seibert, Yong-Xiang Chen, Tieqiang Hu, Chunhua Shi, Xiaoling Zhao, Charles M. Cuerrier, Joshua E. Raizman, and Edward R. O’Brien. "Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages." Cell Stress and Chaperones 18, no. 1 (August 1, 2012): 53–63. http://dx.doi.org/10.1007/s12192-012-0356-0.
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Whitham, Martin, Gary J. Walker, and Nicolette C. Bishop. "Effect of caffeine supplementation on the extracellular heat shock protein 72 response to exercise." Journal of Applied Physiology 101, no. 4 (October 2006): 1222–27. http://dx.doi.org/10.1152/japplphysiol.00409.2006.
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The stimulus for the release of 72-kDa heat shock protein (HSP72) during exercise in humans is currently unclear. Recent evidence in an animal model is suggestive of an involvement of catecholamines. The present study, therefore, investigated the effect of caffeine supplementation, a known stimulator of sympathetic activity, on the extracellular (e)HSP72 response to prolonged exercise. Ten healthy male endurance-trained cyclists were recruited (age: 21 ± 1 yr, maximum O2 uptake 61.1 ± 1.7 ml·kg−1·min−1, mean ± SE). Each subject was randomly assigned to ingest either 6 mg/kg body mass of caffeine (Caff) or placebo (Pla) 60 min before one of two 90-min bouts of cycling at 74 ± 1% maximum O2 uptake. Trials were performed at least 7 days apart in a counterbalanced design. Venous blood samples were collected by venepuncture at pretreatment, preexercise, postexercise, and 1 h postexercise. Serum caffeine and plasma catecholamines were determined using a spectrophotometric assay and high-performance liquid chromatography, respectively. Plasma HSP72 and cortisol were determined by ELISA. Serum caffeine concentrations were significantly increased throughout Caff, while no increases were detected in Pla. Caffeine supplementation and exercise was associated with a greater eHSP72 response than exercise alone (postexercise Caff 8.6 ± 1.3 ng/ml; Pla 5.9 ± 0.9 ng/ml). This greater eHSP72 response was associated with a greater epinephrine response to exercise in Caff. There was a significant increase in norepinephrine and cortisol, with no intertrial differences. The present data suggest that, in humans, catecholamines may be an important mediator of the exercise-induced increase in eHSP72 concentration.
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Archer, Ashley E., Alex T. Von Schulze, and Paige C. Geiger. "Exercise, heat shock proteins and insulin resistance." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1738 (December 4, 2017): 20160529. http://dx.doi.org/10.1098/rstb.2016.0529.
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Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs. 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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Evdonin, Anton, Alexander Kinev, Natalia Tsupkina, Vince Guerriero, Deborah A. Raynes, and Natalia Medvedeva. "Extracellular HspBP1 and Hsp72 synergistically activate epidermal growth factor receptor." Biology of the Cell 101, no. 6 (June 2009): 351–60. http://dx.doi.org/10.1042/bc20080069.
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Jin, Chunhua, Joseph C. Cleveland, Lihua Ao, Jilin Li, Qingchun Zeng, David A. Fullerton, and Xianzhong Meng. "Human Myocardium Releases Heat Shock Protein 27 (HSP27) after Global Ischemia: The Proinflammatory Effect of Extracellular HSP27 through Toll-like Receptor (TLR)-2 and TLR4." Molecular Medicine 20, no. 1 (January 2014): 280–89. http://dx.doi.org/10.2119/molmed.2014.00058.
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Lunge, Ajitesh, Radhika Gupta, Eira Choudhary, and Nisheeth Agarwal. "The unfoldase ClpC1 of Mycobacterium tuberculosis regulates the expression of a distinct subset of proteins having intrinsically disordered termini." Journal of Biological Chemistry 295, no. 28 (May 14, 2020): 9455–73. http://dx.doi.org/10.1074/jbc.ra120.013456.
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The human pathogen Mycobacterium tuberculosis (Mtb) harbors a well-orchestrated Clp (caseinolytic protease) proteolytic machinery consisting of two oligomeric segments, a barrel-shaped heterotetradecameric protease core comprising the ClpP1 and ClpP2 subunits, and hexameric ring-like ATP-dependent unfoldases composed of ClpX or ClpC1. The roles of the ClpP1P2 protease subunits are well-established in Mtb, but the potential roles of the associated unfoldases, such as ClpC1, remain elusive. Using a CRISPR interference–mediated gene silencing approach, here we demonstrate that clpC1 is indispensable for the extracellular growth of Mtb and for its survival in macrophages. The results from isobaric tags for relative and absolute quantitation–based quantitative proteomic experiments with clpC1- and clpP2-depleted Mtb cells suggested that the ClpC1P1P2 complex critically maintains the homeostasis of various growth-essential proteins in Mtb, several of which contain intrinsically disordered regions at their termini. We show that the Clp machinery regulates dosage-sensitive proteins such as the small heat shock protein Hsp20, which exists in a dodecameric conformation. Further, we observed that Hsp20 is poorly expressed in WT Mtb and that its expression is greatly induced upon depletion of clpC1 or clpP2. Remarkably, high Hsp20 protein levels were detected in the clpC1(−) or clpP2(−) knockdown strains but not in the parental bacteria, despite significant induction of hsp20 transcripts. In summary, the cellular levels of oligomeric proteins such as Hsp20 are maintained post-translationally through their recognition, disassembly, and degradation by ClpC1, which requires disordered ends in its protein substrates.
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Abell, Amy N., Jaime A. Rivera-Perez, Bruce D. Cuevas, Mark T. Uhlik, Susan Sather, Nancy L. Johnson, Suzanne K. Minton, et al. "Ablation of MEKK4 Kinase Activity Causes Neurulation and Skeletal Patterning Defects in the Mouse Embryo." Molecular and Cellular Biology 25, no. 20 (October 15, 2005): 8948–59. http://dx.doi.org/10.1128/mcb.25.20.8948-8959.2005.
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ABSTRACT Skeletal disorders and neural tube closure defects represent clinically significant human malformations. The signaling networks regulating normal skeletal patterning and neurulation are largely unknown. Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4K1361R). Embryos homozygous for this mutation die at birth as a result of skeletal malformations and neural tube defects. Hindbrains of exencephalic MEKK4K1361R embryos show a striking increase in neuroepithelial cell apoptosis and a dramatic loss of phosphorylation of MKK3 and -6, mitogen-activated protein kinase kinases (MKKs) regulated by MEKK4 in the p38 pathway. Phosphorylation of MAPK-activated protein kinase 2, a p38 substrate, is also inhibited, demonstrating a loss of p38 activity in MEKK4K1361R embryos. In contrast, the MEK1/2-extracellular signal-regulated kinase 1 (ERK1)/ERK2 and MKK4-Jun N-terminal protein kinase pathways were unaffected. The p38 pathway has been shown to regulate the phosphorylation and expression of the small heat shock protein HSP27. Compared to the wild type, MEKK4K1361R fibroblasts showed significantly reduced phosphorylation of p38 and HSP27, with a corresponding heat shock-induced instability of the actin cytoskeleton. Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation.
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Solly, Françoise, Pascale Flandrin-Gresta, Carmen Aanei, Jérôme Cornillon, Emmanuelle Tavernier, Denis Guyotat, and Lydia Campos. "High Levels of Heat Shock Proteins 90 and 27 in CD34-Positive Cells from Myelodysplastic Syndromes (MDS) Are Associated with Higher Expression and Activation of Focal Adhesion Kinase (FAK) and with Disease Progression." Blood 114, no. 22 (November 20, 2009): 289. http://dx.doi.org/10.1182/blood.v114.22.289.289.
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Abstract Abstract 289 MDS are characterized by a high risk of evolution into acute myeloid leukemia (AML). The pathogenesis of this evolution is still unclear. Some studies indicate that aberrant activation of survival signaling pathways is involved. The 90-kDa heat shock protein (HSP90) is implicated in the conformational maturation and stabilization of protein kinases and has key roles in signal transduction, protein folding, and protein degradation. HSP90 levels are increased in AML cells, and associated with resistance to chemotherapy induced apoptosis. Moreover, HSP90 is involved in the formation of focal adhesions. Focal Adhesion Kinase (FAK), a non-receptor tyrosine kinase, and a client of HSP90, is a member of the integrin-mediated signal transduction pathway. FAK was found over-expressed and constitutively activated in solid tumors. In AML, FAK expression is associated with enhanced blast migration and poor prognosis. FAK also exerts a potent antiapoptotic effect through adhesion to extracellular matrix and stromal cells. Finally 27-kDa heat shock protein (HSP27), a small HSP, prevents apoptosis by interfering with the mitochondrial pathway of apoptosis. In a cancer cell line, HSP27 has been shown to regulate cell adhesion via modulation of FAK. The aim of our study was to investigate the role of HSP90 in high-risk MDS and its potential role on focal adhesion. The expression of HSP90, HSP27, phosphorylated FAK (pFAK), and phosphorylated Akt (pAkt) was assessed by multicolor flow cytometry in bone marrow (BM) mononuclear (MNC) and CD34+ cells from 177 MDS samples at diagnosis: 96 refractory anemias with excess of blasts (RAEB), 58 refractory anemias (RA) and 23 chronic myelomonocytic leukemias (CMML). The levels of HSP90, HSP27, FAK, pFAK, and pAkt in MNC from RAEB patients, were significantly higher than in those measured in RA or CMML patients (p<10−5) (Table). The same difference was observed in CD34+ cells, showing that the increased levels observed in RAEB MNC were not a consequence of increased percentage of blasts. In control marrows (n=5), the percentages of positive cells in MNC and CD34+ populations were similar to that in RA. The percentages of HSP90, HSP27, FAK, pFAK and pAKT were significantly correlated with those of blasts and CD34+ cells, and tended to be higher in cases with high-risk cytogenetics. Consequently the risk of transformation into AML was significantly higher when these proteins were highly expressed. The effects of inhibition of HSP90 were evaluated in 30 RAEB samples by incubating MNC with 17-Alyl-amino-gelgenamycin (17-AAG) at concentrations of 1 and 5μM for 24 hours in liquid culture. A downregulation of HSP90, pFAK and pAKT was observed in CD34+ cells at 12 hours, followed by increased apoptosis at 24h as assessed by activated caspase 3 and annexin V staining. Our results suggest that FAK, HSP90 and Akt activation are associated with cell survival and may contribute to the progression of MDS to leukemia. Moreover this signaling network could be a therapeutic target through HSP90 inhibition by 17-AAG. Disclosures: No relevant conflicts of interest to declare.
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Abboud, Patricia A., Patrick M. Lahni, Kristen Page, John S. Giuliano, Kelli Harmon, Katherine E. Dunsmore, Hector R. Wong, and Derek S. Wheeler. "THE ROLE OF ENDOGENOUSLY PRODUCED EXTRACELLULAR HSP72 IN MONONUCLEAR CELL REPROGRAMMING." Shock 30, no. 3 (September 2008): 285–92. http://dx.doi.org/10.1097/shk.0b013e318164e2c3.
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Gabai, Vladimir L., Julia A. Yaglom, Vladimir Volloch, Anatoli B. Meriin, Thomas Force, Maria Koutroumanis, Bernard Massie, Dick D. Mosser, and Michael Y. Sherman. "Hsp72-Mediated Suppression of c-Jun N-Terminal Kinase Is Implicated in Development of Tolerance to Caspase-Independent Cell Death." Molecular and Cellular Biology 20, no. 18 (September 15, 2000): 6826–36. http://dx.doi.org/10.1128/mcb.20.18.6826-6836.2000.
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ABSTRACT Pretreatment with mild heat shock is known to protect cells from severe stress (acquired thermotolerance). Here we addressed the mechanism of this phenomenon by using primary human fibroblasts. Severe heat shock (45°C, 75 min) of the fibroblasts caused cell death displaying morphological characteristics of apoptosis; however, it was caspase independent. This cell death process was accompanied by strong activation of Akt, extracellular signal-regulated kinase 1 (ERK1) and ERK2, p38, and c-Jun N-terminal (JNK) kinases. Suppression of Akt or ERK1 and -2 kinases increased cell thermosensitivity. In contrast, suppression of stress kinase JNK rendered cells thermoresistant. Development of thermotolerance was not associated with Akt or ERK1 and -2 regulation, and inhibition of these kinases did not reduce acquired thermotolerance. On the other hand, acquired tolerance to severe heat shock was associated with downregulation of JNK. Using an antisense-RNA approach, we found that accumulation of the heat shock protein Hsp72 is necessary for JNK downregulation and is critical for thermotolerance. The capability of naive cells to withstand moderate heat treatment also appears to be dependent on the accumulation of Hsp72 induced by this stress. Indeed, exposure to 45°C for 45 min caused only transient JNK activation and was nonlethal, while prevention of Hsp72 accumulation prolonged JNK activation and led to massive cell death. We also found that JNK activation by UV irradiation, interleukin-1, or tumor necrosis factor was suppressed in thermotolerant cells and that Hsp72 accumulation was responsible for this effect. Hsp72-mediated suppression of JNK is therefore critical for acquired thermotolerance and may play a role in tolerance to other stresses.
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Takamatsu, Hiroyuki, Zhirong Qi, Tomoyuki Sakurai, Luis Espinoza, Naomi Sugimori, Hirohito Yamazaki, Katsuya Okawa, and Shinji Nakao. "Identification of a Novel Auto-Antibody Highly Prevalent in Patients with Hepatitis-Associated and Idiopathic Aplastic Anemia." Blood 114, no. 22 (November 20, 2009): 3200. http://dx.doi.org/10.1182/blood.v114.22.3200.3200.
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Abstract Abstract 3200 Poster Board III-137 Hepatitis-associated aplastic anemia (HAA) is a subset of acquired AA that is highly responsive to immunosuppressive therapy. The target antigens of the immune system attack in HAA are thought to be a protein shared by both liver and hematopoietic stem cells, since it is usually associated with severe hepatitis of unknown etiology. Screening sera from patients with HAA for the presence of antibodies (Abs) recognizing liver cell-derived proteins may be useful in identifying novel auto-antigens in AA. To test this hypothesis, sera from HAA patients were examined using immunoblotting with a lysate of a hepatocellular carcinoma cell line Huh7 and subsequent peptide mass fingerprinting. Methods and Results The serum of a patient with typical HAA (a 23 year-old male) possessing a small population of paroxysmal nocturnal hemoglobinuria (PNH)-type cells was used for Western blotting (WB) with the lysates of Huh7. A distinct band of 70 kDa protein was revealed. The same band was revealed when the culture supernatant of Huh7 cells was subjected to WB. The peptide mass fingerprinting of the 70 kDa band identified this protein to be heat shock protein (HSP) 72. HSP72 is a stress-inducible protein and extracellular HSP72 enhances the cytotoxicity of CD4+ T cells and NK cells. An examination of the sera from HAA patients, idiopathic acquired AA (IAA) patients and healthy individuals with WB revealed the anti-HSP72 Abs to be detected in 10 of 12 (83%) HAA patients and in 57 of 80 (71%) IAA patients while it was detected only in 8 of 59 (14%) healthy individuals. The prevalence of anti-HSP72 Abs in AA was markedly higher than that of anti-kinectin Abs (39%), anti-PMS1 Abs (10%), anti-DRS-1 Abs (38%) or anti-moesin Abs (37%) reported previously. Anti-HSP72 Abs were frequently detectable both in patients with IAA possessing PNH-type cells (63%) and in patients without PNH-type cells (86%), a finding contrasting to the higher prevalence of anti-DRS-1 Abs and anti-moesin Abs in patients with PNH-type cells than in those without PNH-type cells reported previously. Although anti-HSP72 Abs were detectable in the sera of patients with rheumatoid arthritis and systemic lupus erythematosus, the prevalence was 15% (4 of 27) and 20% (1 of 5), respectively. In contrast to a previous report that detected anti-HSP72 Abs in 24% of patients with chronic hepatitis C, WB failed to detect the Abs in the sera of 4 patients with autoimmune hepatitis and 5 with hepatitis B or C. Ten patients with HAA were treated with immunosuppressive therapy, and 7 of the 8 responders expressed anti-HSP72 Abs. The quantification of the gene expression level of HSP72 by blood cells using real-time PCR demonstrated that the HSP72 mRNA levels were markedly higher in myeloid leukemia cell lines as well as CD34+ cells isolated from 3 healthy individuals in comparison to that in lymphoid or monocytoid leukemia cell lines. HSP72/GAPDH ratios of PBMCs and CD34+ cells from 3 healthy individuals, K562, KH88, OUN-1 were 0.51, 1.31, 1.02, 0.07 and 0.09 respectively. Other leukemia cell lines such as Daudi, Molt-4 and THP-1 did not display detectable levels of HSP72 mRNA. The cell surface expression of HSP72 was examined in various kinds of leukemia cell lines and CD34+ bone marrow (BM) cells derived from 3 healthy individuals using Ab to HSP72 (Clone C92F3A-5) because previous studies demonstrated heat-inducible expression of HSP72 by K562. Flow cytometry detected cell surface HSP72 on immature CML cell lines such as K562 but not on CD34+ BM cells, acute promyelocytic leukemia cell lines such as NB-4 and HL-60, and lymphoid leukemia cell lines such as Molt-4 and Daudi. Exposure to 42°C for 2 h increased the HSP72 expression on K562 cells and Molt-4 cells but not on CD34+ cells. Conclusion Anti-HSP72 Ab is the most prevalent auto-Ab in AA among the auto-Abs previously detected. Given the increased expression of HSP72 by immature myeloid cells as well as stress-inducible cell surface expression of the molecule, immune responses to HSP72 may thus play an essential role in the pathogenesis of HAA and IAA. Disclosures No relevant conflicts of interest to declare.
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Luo, Hongyang, Taixiang Liu, Huasheng Yang, Huijing Ye, and Xin Luo. "Expression of Collagen (Types I, III, and V), HSP47, MMP-2, and TIMP-1 in Retrobulbar Adipose Tissue of Patients with Thyroid-Associated Orbitopathy." Journal of Ophthalmology 2020 (April 23, 2020): 1–5. http://dx.doi.org/10.1155/2020/4929634.
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Objective. This study aimed to investigate the expression of collagen (types I, III, and V), heat shock protein 47 (HSP47), matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase-1 (TIMP-1) in the retrobulbar adipose tissues of patients with thyroid-associated orbitopathy (TAO). Materials and Methods. The retrobulbar adipose tissues were collected from 4 TAO patients undergoing orbital decompression and 4 ocular enucleation patients with atrophic eyeball caused by ocular trauma between May 2019 and September 2019. Masson staining was performed to analyze the differences in collagen expression and degree of histologic fibrosis in each sample. The protein expressions of collagen (types I, III, and V), HSP47, MMP-2, and TIMP-1 were determined by western blotting. The data of western blotting were analyzed using SPSS version 17.0, with independent t-tests. Results. The results of Masson staining showed that the expression of collagen fibers in the TAO group was significantly higher than that in the control group, and the fibers were diffuse and irregular in distribution. The expression level of collagen (types I, III, and V), HSP47, MMP-2, and TIMP-1 in the TAO group were significantly higher than that in the control group (P<0.05). Conclusion. The proliferation and fibrosis of retrobulbar adipose tissue in TAO patients might be related to the increased expression of collagen (types I, III, and V) and HSP47 and decreased degradation of extracellular matrix.
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Thienel, Manuela, Johannes B. Müller-Reif, Zhe Zhang, Vincent Ehreiser, Judith Huth, Khrystyna Shchurovska, Badr Kilani, et al. "Immobility-associated thromboprotection is conserved across mammalian species from bear to human." Science 380, no. 6641 (April 14, 2023): 178–87. http://dx.doi.org/10.1126/science.abo5044.
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Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry–based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.