Journal articles: 'Extracellular HSP27'

1

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.

3

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.

4

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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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.

7

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.

8

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.

9

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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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.

12

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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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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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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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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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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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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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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Zheng, Guopei, Zhijie Zhang, Hao Liu, Yan Xiong, Liyun Luo, Xiaoting Jia, Cong Peng, et al. "HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue." Clinical Cancer Research 24, no. 5 (December 15, 2017): 1163–75. http://dx.doi.org/10.1158/1078-0432.ccr-17-2619.

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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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Joo, Jin Deok, Mihwa Kim, Patrick Horst, Jeehee Kim, Vivette D. D'Agati, Charles W. Emala, and H. Thomas Lee. "Acute and delayed renal protection against renal ischemia and reperfusion injury with A1 adenosine receptors." American Journal of Physiology-Renal Physiology 293, no. 6 (December 2007): F1847—F1857. http://dx.doi.org/10.1152/ajprenal.00336.2007.

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We showed previously that activation of A1 adenosine receptors (AR) protects against renal ischemia-reperfusion (IR) injury in rats and mice. In the heart, transient A1AR activation produces biphasic protective effects: acute protection wanes after several hours but protective effects return 24–72 h later (second window of protection). In this study, we determined whether A1AR activation produces delayed renal protection and elucidated the mechanisms of acute and delayed renal protection. A1AR wild-type mice were subjected to 30-min renal ischemia and 24 h of reperfusion to produce acute renal failure. Pretreatment with a selective A1AR agonist 2-chloro- N6-cyclopentyladenosine (CCPA; 0.1 mg/kg bolus ip) either 15 min or 24 h before renal ischemia protected against renal IR injury and reduced renal corticomedullary necrosis, apoptosis, and inflammation. Transient A1AR activation led to phosphorylation of extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK), Akt, and heat shock protein 27 (HSP27). Moreover, induction of HSP27 and Akt occurred with CCPA treatment. Inhibition of PKC with chelerythrine prevented acute but not delayed renal protection with A1AR activation. Moreover, deletion of PI3Kγ or inhibition of Akt, but not inhibition of ERK, prevented delayed and acute renal protection with A1AR activation. Inhibition of Gi/o with pertussis toxin obliterated both acute and delayed A1AR-mediated renal protection. In contrast to renal protection with delayed ischemic preconditioning, nitric oxide synthase activity was not induced with delayed A1AR-mediated renal protection. Therefore, transient activation of renal A1AR led to acute as well as delayed protective effects against renal IR injury via distinct signaling pathways.

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Ao, Lihua, Yufeng Zhai, Chunhua Jin, Joseph C. Cleveland, David A. Fullerton, and Xianzhong Meng. "Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4." Molecular Medicine 22, no. 1 (January 2016): 863–72. http://dx.doi.org/10.2119/molmed.2016.00204.

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Lee, J., J. Kim, J. Choi, J. Lee, B. Lee, and J. Park. "Abstract: P232 HSP27 MODULATES OXIDIZED LDL INDUCED DESTRUCTION AND SYNTHESIS OF EXTRACELLULAR MATRIX IN VASCULAR SMOOTH MUSCLE CELLS." Atherosclerosis Supplements 10, no. 2 (June 2009): e297. http://dx.doi.org/10.1016/s1567-5688(09)70297-1.

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Dave, Kandarp M., Donna B. Stolz, Venugopal R. Venna, Victoria A. Quaicoe, Michael E. Maniskas, Michael John Reynolds, Riyan Babidhan, et al. "Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures." Journal of Controlled Release 354 (February 2023): 368–93. http://dx.doi.org/10.1016/j.jconrel.2023.01.025.

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Dempsey, Nina C., Francesca Leoni, John H. H. Williams, and Christine Hoyle. "Heat Shock Protein Localisation in Chronic Lymphatic Leukaemia." Blood 112, no. 11 (November 16, 2008): 2085. http://dx.doi.org/10.1182/blood.v112.11.2085.2085.

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Abstract Heat Shock Proteins (Hsps) are a highly conserved group of molecular chaperones, the over-expression of which has been well documented in many cancer types. However, the location of these proteins within the cancer cell appears to be crucial in terms of tumour progression. Intracellular Hsp70 expression in particular appears to confer resistance to apoptosis, while surface Hsp70 expression has been shown to aid immune recognition of the cancer cell by NK cells. High intracellular levels of Hsp90 and Hsp27 also contribute to cell survival, while surface Hsp90 and Hsp27 have been shown to be required for tissue invasion and metastasis. However, the importance of these stress proteins in CLL progression is still poorly understood. Using flow cytotmetry, we show that CLL patients express significantly higher levels of iHsp90 in lymphocytes (mean MFI CLL = 2463, Control = 748) and significantly higher levels of iHsp27 in lymphocytes (mean MFI CLL = 2138, Control = 760) than that expressed by age-matched control patients. The expression of iHsp90, but not Hsp27, in these patients was shown to be related to the stage of disease, and patients in Binet stage A appear to have a significantly higher expression than those in Binet stage C (p<0.001). Hsp70 expression in CD5+/CD19+ cells, both intracellular and extracellular, showed either a very high level or a very low level of Hsp70 (see figure below). The high expressing groups were found also to be significantly different (p<0.01) from both the non-malignant cells from the same patients, and normal lymphocytes from age-matched controls. This was not the case for the low expressing groups. iHsp70 expression was also seen to be related to stage of disease as patients in Binet stages A and B were found to express significantly lower levels than those patients in Binet stage C. Hsp expression was shown not to be associated with the apoptotic condition of the cell as analysis of active caspase-3 in CLL patients proved that the majority of the leukocytes were not apoptotic. Furthermore, the mean of fluorescence was significantly less in lymphocytes from CLL patients (mean MFI = 139) than those from control patients (mean MFI = 278). Taken together these results show that Hsp expression changes with the natural progression of the disease and therefore manipulation of Hsps may be beneficial in the treatment of CLL. Figure Figure

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Kostrzewa-Nowak, Dorota, Andrzej Ciechanowicz, Jeremy S. C. Clark, and Robert Nowak. "Damage-Associated Molecular Patterns and Th-Cell-Related Cytokines Released after Progressive Effort." Journal of Clinical Medicine 9, no. 3 (March 23, 2020): 876. http://dx.doi.org/10.3390/jcm9030876.

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Inflammation-induced processes commence with the activation of signalling pathways at the cellular level, which mobilize inflammatory cells and stimulate the secretion of chemokines, cytokines, and damage-associated molecular pattern molecules (DAMPs). Physical effort stimulates inflammation, contributing to muscle repair and regeneration. We have examined the impact of different protocols of progressive-effort tests on T-cell DAMP levels, extracellular cleavage products (fibronectin and hyaluronan), and Th-cell-related cytokine levels among soccer players. Thirty male soccer players with a median age of 17 (16–22) years performed different defined protocols for progressive exercise until exhaustion: (1) YO-YO intermittent recovery test level 1 (YYRL1, n = 10); (2) maximal multistage 20 m shuttle run (Beep, n = 10); and mechanical treadmill (MT, n = 10); and (3) shuttle-run test (n = 10). Blood samples were taken three times as follows: at baseline, post effort, and in recovery. Significantly higher post-effort concentrations of IL-4, IL-6, IL-10, and IFN-γ were observed in the Beep group, IL-4 in the YYRL1 group, and IL-6 and IFN-γ in the MT group as compared with the baseline values. Recovery values were significantly higher for concentrations of IL-4, IL-10, and IFN-γ in the YYRL1 group, only for IFN-γ in the Beep group, and for IL-6, IL-10, and INF-γ in the MT group as compared with the baseline values. Post-effort concentrations of DEFβ2, Hsp27, Fn, and UA in the Beep group and Hsp27 and HA in the YYRL1 group were significantly higher as compared with the baseline values. It seems the performed efficiency test protocols caused a short-term imbalance in Th1/Th2 cytokine levels without giving common molecular patterns. The rapidity of these changes was apparently related to specific physical movements and the type of running surface.

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Schwab, Melissa, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Caroline Werner, Maxim Shevtsov, Tommaso Di Genio, et al. "Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response." Cancers 13, no. 15 (July 27, 2021): 3762. http://dx.doi.org/10.3390/cancers13153762.

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The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH−/−) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.

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An, Steven S., Corin M. Pennella, Achuta Gonnabathula, Jianxin Chen, Ning Wang, Matthias Gaestel, Paul M. Hassoun, Jeffrey J. Fredberg, and Usamah S. Kayyali. "Hypoxia alters biophysical properties of endothelial cells via p38 MAPK- and Rho kinase-dependent pathways." American Journal of Physiology-Cell Physiology 289, no. 3 (September 2005): C521—C530. http://dx.doi.org/10.1152/ajpcell.00429.2004.

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Hypoxia alters the barrier function of the endothelial cells that line the pulmonary vasculature, but underlying biophysical mechanisms remain unclear. Using rat pulmonary microvascular endothelial cells (RPMEC) in culture, we report herein changes in biophysical properties, both in space and in time, that occur in response to hypoxia. We address also the molecular basis of these changes. At the level of the single cell, we measured cell stiffness, the distribution of traction forces exerted by the cell on its substrate, and spontaneous nanoscale motions of microbeads tightly bound to the cytoskeleton (CSK). Hypoxia increased cell stiffness and traction forces by a mechanism that was dependent on the activation of Rho kinase. These changes were followed by p38-mediated decreases in spontaneous bead motions, indicating stabilization of local cellular-extracellular matrix (ECM) tethering interactions. Cells overexpressing phospho-mimicking small heat shock protein (HSP27-PM), a downstream effector of p38, exhibited decreases in spontaneous bead motions that correlated with increases in actin polymerization in these cells. Together, these findings suggest that hypoxia differentially regulates endothelial cell contraction and cellular-ECM adhesion.

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Timofeev, Yuriy S., Anton R. Kiselev, Olga N. Dzhioeva, and Oxana M. Drapkina. "Heat Shock Proteins (HSPs) and Cardiovascular Complications of Obesity: Searching for Potential Biomarkers." Current Issues in Molecular Biology 45, no. 12 (November 23, 2023): 9378–89. http://dx.doi.org/10.3390/cimb45120588.

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Heat shock proteins (HSPs), a family of proteins that support cellular proteostasis and perform a protective function under various stress conditions, such as high temperature, intoxication, inflammation, or tissue hypoxia, constitute a promising group of possible biochemical markers for obesity and cardiovascular diseases. HSP27 is involved in essential cellular processes occurring in conditions of obesity and its cardiometabolic complications; it has protective properties, and its secretion may indicate a cellular response to stress. HSP40 plays a controversial role in the pathogenesis of obesity. HSP60 is involved in various pathological processes of the cardiovascular, immune, excretory, and nervous systems and is associated with obesity and concomitant diseases. The hypersecretion of HSP60 is associated with poor prognosis; hence, this protein may become a target for further research on obesity and its cardiovascular complications. According to most studies, intracellular HSP70 is an obesity-promoting factor, whereas extracellular HSP70 exhibited inconsistent dynamics across different patient groups and diagnoses. HSPs are involved in the pathogenesis of cardiovascular pathology. However, in the context of cardiovascular and metabolic pathology, these proteins require further investigation.

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Wantoch von Rekowski, Kathleen, Philipp König, Svenja Henze, Martin Schlesinger, Piotr Zawierucha, Radosław Januchowski, and Gerd Bendas. "Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies." International Journal of Molecular Sciences 21, no. 23 (December 3, 2020): 9240. http://dx.doi.org/10.3390/ijms21239240.

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The microenvironment possesses a strong impact on the tumor chemoresistance when cells bind to components of the extracellular matrix. Here we elucidate the signaling pathways of cisplatin resistance in W1 ovarian cancer cells binding to collagen type 1 (COL1) and signaling interference with constitutive cisplatin resistance in W1CR cells to discover the targets for sensitization. Proteome kinase arrays and Western blots were used to identify the signaling components, their impact on cisplatin resistance was evaluated by inhibitory or knockdown approaches. W1 cell binding to COL1 upregulates integrin-associated signals via FAK/PRAS40/mTOR, confirmed by β1-integrin (ITGB1) knockdown. mTOR appears as key for resistance, its blockade reversed COL1 effects on W1 cell resistance completely. W1CR cells compensate ITGB1-knockdown by upregulation of discoidin domain receptor 1 (DDR1) as alternative COL1 sensor. COL1 binding via DDR1 activates the MAPK pathway, of which JNK1/2 appears critical for COL1-mediated resistance. JNK1/2 inhibition inverts COL1 effects in W1CR cells, whereas intrinsic cisplatin resistance remained unaffected. Remarkably, knockdown of HSP27, another downstream MAPK pathway component overcomes intrinsic resistance completely sensitizing W1CR cells to the level of W1 cells for cisplatin cytotoxicity. Our data confirm the independent regulation of matrix-induced and intrinsic chemoresistance in W1 ovarian cancer cells and offer novel targets for sensitization.

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Monda, Marcellino, Giovanni Messina, Ilaria Scognamiglio, Angela Lombardi, Giuseppe A. Martin, Pasquale Sperlongano, Marina Porcelli, Michele Caraglia, and Paola Stiuso. "Short-Term Diet and Moderate Exercise in Young Overweight Men Modulate Cardiocyte and Hepatocarcinoma Survival by Oxidative Stress." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/131024.

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The present study was designed to evaluate the effects of diet lifestyle on extending lifespan and reducing liver cancer risk. Young overweight men(n=20), without metabolic syndrome, were placed in a 3-week residential program on a low-fat diet and moderate aerobic exercise. In each subject, pre- and postintervention fasting blood were collected for evaluating levels of serum lipids, and oxidative stress markers. Using subject sera and cardiomyocyte (H9C2) culture systems, we measured heat shock protein 27 and 90 expression, lipid accumulation, and oxidative stress marker levels. After 3-weeks of diet, significant reductions(P<0.05)in body mass index, serum lipids and lipid ratios, and oxidative markers were recorded.In vitro, we observed that the addition of postintervention sera increased H9C2 cell number and reduced HSP27 and 90 expression, mitochondrial superoxide anion, and lipid accumulation with a parallel increase in nitric oxide (NO) production (allP<0.01). At the same time, postintervention sera decreased human liver hepatocellular carcinoma cell line (HepG-2) proliferation, lipid accumulation, oxidative stress, and extracellular-signal-regulated kinases (ERK1/2) activity. Lifestyle modification in young overweight men, without metabolic syndrome, could ameliorate cardiocyte survival and reduce hepatocellular carcinoma cell proliferation.

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Tanabe, Hiroki, Takuji Suzuki, Tomokazu Ohishi, Mamoru Isemura, Yoriyuki Nakamura, and Keiko Unno. "Effects of Epigallocatechin-3-Gallate on Matrix Metalloproteinases in Terms of Its Anticancer Activity." Molecules 28, no. 2 (January 5, 2023): 525. http://dx.doi.org/10.3390/molecules28020525.

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Epidemiological studies have shown that the consumption of green tea has beneficial effects against cancer. Basic studies have provided evidence that epigallocatechin gallate (EGCG) is a major contributor to these effects. Matrix metalloproteinases (MMPs) are zinc-dependent metalloproteinases with the ability to degrade the extracellular matrix proteins and are involved in various diseases including cancer in which MMPs have a critical role in invasion and metastasis. In this review, we discuss the effects of EGCG on several types of MMPs in the context of its anticancer activity. In the promoter region, MMPs have binding sites for at least one transcription factor of AP-1, Sp1, and NF-κB, and EGCG can downregulate these transcription factors through signaling pathways mediated by reactive oxygen species. EGCG can also decrease nuclear ERK, p38, heat shock protein-27 (Hsp27), and β-catenin levels, leading to suppression of MMPs’ expression. Other mechanisms by which EGCG inhibits MMPs include direct binding to MMPs to prevent their activation and downregulation of NF-κB to suppress the production of inflammatory cytokines such as TNFα and IL-1β. Findings from studies on EGCG presented here may be useful in the development of more effective anti-MMP agents, which would give beneficial effects on cancer and other diseases.

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Shi, Yu, Alexey Kotlyarov, Kathrin Laaß, Achim D. Gruber, Elke Butt, Katrin Marcus, Helmut E. Meyer, Anke Friedrich, Hans-Dieter Volk, and Matthias Gaestel. "Elimination of Protein Kinase MK5/PRAK Activity by Targeted Homologous Recombination." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7732–41. http://dx.doi.org/10.1128/mcb.23.21.7732-7741.2003.

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ABSTRACT MK5 (mitogen-activated protein kinase [MAPK]-activated protein kinase 5), also designated PRAK (p38-regulated and -activated kinase), was deleted from mice by homologous recombination. Although no MK5 full-length protein and kinase activity was detected in the MK5 knockout mice, the animals were viable and fertile and did not display abnormalities in tissue morphology or behavior. In addition, these mice did not show increased resistance to endotoxic shock or decreased lipopolysaccharide-induced cytokine production. Hence, MK5 deletion resulted in a phenotype very different from the complex inflammation-impaired phenotype of mice deficient in MK2, although MK2 and MK5 exhibit evolutional, structural, and apparent extensive functional similarities. To explain this discrepancy, we used wild-type cells and embryonic fibroblasts from both MK2 and MK5 knockout mice as controls to reexamine the mechanism of activation, the interaction with endogenous p38 MAPK, and the substrate specificity of both enzymes. In contrast to MK2, which shows interaction with and chaperoning properties for p38 MAPK and which is activated by extracellular stresses such as arsenite or sorbitol treatment, endogenous MK5 did not show these properties. Furthermore, endogenous MK5 is not able to phosphorylate Hsp27 in vitro and in vivo. We conclude that the differences between the phenotypes of MK5- and MK2-deficient mice result from clearly different functional properties of both enzymes.

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Weiss, Louis M., Yan Fen Ma, Peter M. Takvorian, Herbert B. Tanowitz, and Murray Wittner. "Bradyzoite Development in Toxoplasma gondii and the hsp70 Stress Response." Infection and Immunity 66, no. 7 (July 1, 1998): 3295–302. http://dx.doi.org/10.1128/iai.66.7.3295-3302.1998.

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ABSTRACT Toxoplasma gondii is a well-described ubiquitous Apicomplexan protozoan parasite that is an important opportunistic pathogen. The factors affecting the transition of tachyzoites to the latent bradyzoite stage remain to be defined. The induction of bradyzoite development in vitro has been linked to temperature, pH, mitochondrial inhibitors, sodium arsenite, and many of the other stressors associated with heat shock protein (hsp) induction. There is evidence for other organisms that hsps are developmentally regulated. Therefore, we examined whether hsp induction is an early event in bradyzoite differentiation. Extracellular and intracellular T. gondii cells, after exposure to pH 8.1 or 7.1, were analyzed for the expression of inducible hsp70 by using monoclonal antibody C92F3A-5 (specific to hsp70). Western blotting demonstrated that a 72-kDa protein reactive with C92F3A-5 (hsp70), which we believe is part of the hsp70 family, is induced during bradyzoite development. By immunofluorescence and immunoelectron microscopy, we were able to demonstrate that hsp70 staining colocalized to T. gondiiexpressing bradyzoite-specific antigens and the presence of hsp70 in bradyzoites isolated from mouse brain. Quercetin, a bioflavonoid which inhibits the synthesis of hsp90, hsp70, and hsp27, suppresses the induction of bradyzoite development in vitro. Reverse transcription-PCR with conserved hsp70 primers demonstrated an increase in hsp70 inT. gondii on exposure to conditions which induce bradyzoite formation. A T. gondii hsp70 was subsequently cloned and sequenced by using this amplified fragment. We believe our evidence suggests that hsps are important in the process of bradyzoite differentiation.

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Voth, Daniel E., and Robert A. Heinzen. "Sustained Activation of Akt and Erk1/2 Is Required for Coxiella burnetii Antiapoptotic Activity." Infection and Immunity 77, no. 1 (November 3, 2008): 205–13. http://dx.doi.org/10.1128/iai.01124-08.

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ABSTRACT Coxiella burnetii is an obligate intracellular bacterial pathogen that directs biogenesis of a lysosome-like, parasitophorous vacuole in mammalian cells. We recently reported that C. burnetii inhibits apoptotic cell death in macrophages, presumably as a mechanism to sustain the host for completion of its lengthy infectious cycle. In the current study, we further investigated C. burnetii manipulation of host cell signaling and apoptosis by examining the effect of C. burnetii infection on activation of 15 host proteins involved in stress responses, cytokine production, and apoptosis. C. burnetii infection of THP-1 human macrophage-like cells caused increased levels of phosphorylated c-Jun, Hsp27, Jun N-terminal protein kinase, and p38 at 2 h postinfection (hpi), and this activation rapidly decreased to near basal levels by 24 hpi. The prosurvival kinases Akt and Erk1/2 (extracellular signal-regulated kinases 1 and 2) were also activated at 2 to 6 hpi; however, the phosphorylation of these proteins increased coincident with C. burnetii replication through at least 72 hpi. Sustained phosphorylation of Akt and Erk1/2 was abolished by treatment of infected cells with rifampin, indicating their activation is a C. burnetii-directed event requiring pathogen RNA synthesis. Moreover, pharmacological inhibition of Akt or Erk1/2 significantly decreased C. burnetii antiapoptotic activity. Collectively, these results indicate the importance of C. burnetii modulation of host signaling and demonstrate a critical role for Akt and Erk1/2 in successful intracellular parasitism and maintenance of host cell viability.

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Desjardins, Pascale, Rébecca Berthiaume, Camille Couture, Gaëtan Le-Bel, Vincent Roy, François Gros-Louis, Véronique J. Moulin, et al. "Impact of Exosomes Released by Different Corneal Cell Types on the Wound Healing Properties of Human Corneal Epithelial Cells." International Journal of Molecular Sciences 23, no. 20 (October 13, 2022): 12201. http://dx.doi.org/10.3390/ijms232012201.

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Corneal wound healing involves communication between the different cell types that constitute the three cellular layers of the cornea (epithelium, stroma and endothelium), a process ensured in part by a category of extracellular vesicles called exosomes. In the present study, we isolated exosomes released by primary cultured human corneal epithelial cells (hCECs), corneal fibroblasts (hCFs) and corneal endothelial cells (hCEnCs) and determined whether they have wound healing characteristics of their own and to which point they modify the genetic and proteomic pattern of these cell types. Exosomes released by all three cell types significantly accelerated wound closure of scratch-wounded hCECs in vitro compared to controls (without exosomes). Profiling of activated kinases revealed that exosomes from human corneal cells caused the activation of signal transduction mediators that belong to the HSP27, STAT, β-catenin, GSK-3β and p38 pathways. Most of all, data from gene profiling analyses indicated that exosomes, irrespective of their cellular origin, alter a restricted subset of genes that are completely different between each targeted cell type (hCECs, hCFS, hCEnCs). Analysis of the genes specifically differentially regulated for a given cell-type in the microarray data using the Ingenuity Pathway Analysis (IPA) software revealed that the mean gene expression profile of hCECs cultured in the presence of exosomes would likely promote cell proliferation and migration whereas it would reduce differentiation when compared to control cells. Collectively, our findings represent a conceptual advance in understanding the mechanisms of corneal wound repair that may ultimately open new avenues for the development of novel therapeutic approaches to improve closure of corneal wounds.

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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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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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Zu, YL, Y. Ai, A. Gilchrist, ME Labadia, RI Sha'afi, and CK Huang. "Activation of MAP kinase-activated protein kinase 2 in human neutrophils after phorbol ester or fMLP peptide stimulation." Blood 87, no. 12 (June 15, 1996): 5287–96. http://dx.doi.org/10.1182/blood.v87.12.5287.bloodjournal87125287.

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In response to extracellular stimulation, one of the earliest events in human neutrophils is protein phosphorylation, which mediates signal transduction and leads to the regulation of cellular functions. Mitogen- activated protein (MAP) kinases are rapidly activated by a variety of mitogens, cytokines, and stresses. The activated MAP kinases in turn regulate their substrate molecules by phosphorylation. MAP kinase- activated protein (MAPKAP) kinase 2, a Ser/Thr kinase, has been shown to be phosphorylated by p38 MAP kinase both in vivo and in vitro. Phosphorylation of the Thr-334 site of MAPKAP kinase 2 results in a conformational change with subsequent activation of the enzyme. To better define the role of MAPKAP kinase 2 in the activation of human neutrophils, its enzymatic activity was measured after stimulation by either a phorbol ester (phorbol myristate acetate [PMA]), a potent protein kinase C activator, or the tripeptide fMLP, which is a chemotactic factor. The in vitro kinase assays indicate that both PMA and fMLP stimulated a transient increase in the enzymatic activity of cellular MAPKAP kinase 2. The induced kinase activation was concentration-dependent and reached a maximum at 5 minutes for PMA and 1 minute for fMLP. To identify potential substrate molecules for MAPKAP kinase 2, a highly active kinase mutant was generated by mutating the MAP kinase phosphorylation site in the C-terminal region. The replacement of threonine 334 with alanine resulted in a marked augmentation of catalytic activity. Analysis of in vitro protein phosphorylation in the presence of the active kinase indicates that a 60-kD cytosolic protein (p60) was markedly phosphorylated and served as the major substrate for MAPKAP kinase 2 in human neutrophils. Based on the MAPKAP kinase 2 phosphorylation site of Hsp27, a competitive inhibitory peptide was synthesized. This competitive inhibitory peptide specifically inhibited MAPKAP kinase 2 enzymatic activity, as well as the in vitro and in vivo kinase-induced p60 phosphorylation. To assess the contribution of MAPKAP kinase 2 in neutrophil function, the oxidative burst response after manipulation of endogenous kinase activity was measured. Intracellular delivery of the competitive inhibitory peptide into human neutrophils reduced both PMA- and fMLP- stimulated superoxide anion production. Thus, the results strongly suggest that MAPKAP kinase 2 is involved in the activation of human neutrophils.

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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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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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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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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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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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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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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.

Journal articles on the topic 'Extracellular HSP27'

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