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The Hexameric Structures of Human Heat Shock Protein 90  [PDF]
Cheng-Chung Lee,Ta-Wei Lin,Tzu-Ping Ko,Andrew H.-J. Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019961
Abstract: The human 90-kDa heat shock protein (HSP90) functions as a dimeric molecular chaperone. HSP90 identified on the cell surface has been found to play a crucial role in cancer invasion and metastasis, and has become a validated anti-cancer target for drug development. It has been shown to self-assemble into oligomers upon heat shock or divalent cations treatment, but the functional role of the oligomeric states in the chaperone cycle is not fully understood.
Heat shock protein 90 in neurodegenerative diseases
Wenjie Luo, Weilin Sun, Tony Taldone, Anna Rodina, Gabriela Chiosis
Molecular Neurodegeneration , 2010, DOI: 10.1186/1750-1326-5-24
Abstract: Hsp90 is a molecular chaperone with important roles in maintaining the functional stability and viability of cells under a transforming pressure [1-3]. For neurodegenerative disorders associated with protein aggregation, the rationale has been that inhibition of Hsp90 activates heat shock factor-1 (HSF-1) to induce production of Hsp70 and Hsp40, as well as of other chaperones, which in turn, promote disaggregation and protein degradation [4-6]. However, recent evidence reveals an additional role for Hsp90 in neurodegeneration. Namely, Hsp90 maintains the functional stability of neuronal proteins of aberrant capacity, thus, allowing and sustaining the accumulation of toxic aggregates [7,8]. Below, we summarize the current understanding on these Hsp90 biological roles and review potential applications of pharmacological Hsp90 inhibition in neurodegenerative diseases.Exposed to conditions of stress, cells normally respond by activation of the heat shock response (HSR) accompanied by increased synthesis of a number of cytoprotective heat shock proteins (Hsps) which dampen cytotoxicity, such as caused by misfolded and denatured proteins [4-6]. The most prominent part of this transition occurs on the transcriptional level. In mammals, protein-damaging stress is regulated by activation of HSF-1, which binds to upstream regulatory sequences in the promoters of heat shock genes [9]. The activation of HSF-1 proceeds through a multi-step pathway, involving a monomer-to-trimer transition, nuclear accumulation and extensive posttranslational modifications (Fig. (1A)). The function of HSF-1 is regulated by Hsp90 [10]. Namely, under non-stressed conditions, Hsp90 binds to HSF-1 and maintains the transcription factor in a monomeric state. Stress, heat shock or inhibition of Hsp90 release HSF-1 from the Hsp90 complex, which results in its trimerization (Fig. (1B)), activation and translocation to the nucleus where it initiates a heat shock response, manifested in the production of H
Modelling the Regulation of Thermal Adaptation in Candida albicans, a Major Fungal Pathogen of Humans  [PDF]
Michelle D. Leach, Katarzyna M. Tyc, Alistair J. P. Brown, Edda Klipp
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032467
Abstract: Eukaryotic cells have evolved mechanisms to sense and adapt to dynamic environmental changes. Adaptation to thermal insults, in particular, is essential for their survival. The major fungal pathogen of humans, Candida albicans, is obligately associated with warm-blooded animals and hence occupies thermally buffered niches. Yet during its evolution in the host it has retained a bona fide heat shock response whilst other stress responses have diverged significantly. Furthermore the heat shock response is essential for the virulence of C. albicans. With a view to understanding the relevance of this response to infection we have explored the dynamic regulation of thermal adaptation using an integrative systems biology approach. Our mathematical model of thermal regulation, which has been validated experimentally in C. albicans, describes the dynamic autoregulation of the heat shock transcription factor Hsf1 and the essential chaperone protein Hsp90. We have used this model to show that the thermal adaptation system displays perfect adaptation, that it retains a transient molecular memory, and that Hsf1 is activated during thermal transitions that mimic fever. In addition to providing explanations for the evolutionary conservation of the heat shock response in this pathogen and the relevant of this response to infection, our model provides a platform for the analysis of thermal adaptation in other eukaryotic cells.
Hsp90 Orchestrates Transcriptional Regulation by Hsf1 and Cell Wall Remodelling by MAPK Signalling during Thermal Adaptation in a Pathogenic Yeast  [PDF]
Michelle D. Leach ,Susan Budge,Louise Walker,Carol Munro,Leah E. Cowen,Alistair J. P. Brown
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1003069
Abstract: Thermal adaptation is essential in all organisms. In yeasts, the heat shock response is commanded by the heat shock transcription factor Hsf1. Here we have integrated unbiased genetic screens with directed molecular dissection to demonstrate that multiple signalling cascades contribute to thermal adaptation in the pathogenic yeast Candida albicans. We show that the molecular chaperone heat shock protein 90 (Hsp90) interacts with and down-regulates Hsf1 thereby modulating short term thermal adaptation. In the longer term, thermal adaptation depends on key MAP kinase signalling pathways that are associated with cell wall remodelling: the Hog1, Mkc1 and Cek1 pathways. We demonstrate that these pathways are differentially activated and display cross talk during heat shock. As a result ambient temperature significantly affects the resistance of C. albicans cells to cell wall stresses (Calcofluor White and Congo Red), but not osmotic stress (NaCl). We also show that the inactivation of MAP kinase signalling disrupts this cross talk between thermal and cell wall adaptation. Critically, Hsp90 coordinates this cross talk. Genetic and pharmacological inhibition of Hsp90 disrupts the Hsf1-Hsp90 regulatory circuit thereby disturbing HSP gene regulation and reducing the resistance of C. albicans to proteotoxic stresses. Hsp90 depletion also affects cell wall biogenesis by impairing the activation of its client proteins Mkc1 and Hog1, as well as Cek1, which we implicate as a new Hsp90 client in this study. Therefore Hsp90 modulates the short term Hsf1-mediated activation of the classic heat shock response, coordinating this response with long term thermal adaptation via Mkc1- Hog1- and Cek1-mediated cell wall remodelling.
Research Progress of Heat Shock Protein 90 and Hepatocellular Carcinoma  [PDF]
Qiyu Jiang, Xiongshan Shen
International Journal of Clinical Medicine (IJCM) , 2020, DOI: 10.4236/ijcm.2020.112005
Abstract: Heat shock protein (HSP) is a kind of protein that mainly acts as a molecular chaperone to participate in the synthesis and folding of proteins, maintain the spatial conformation of proteins and protect cells from damage and other important biological functions. HSP90 plays an important role in maintaining molecular chaperone structure, regulating cell cycle and apoptosis, coordinating hormone signal transduction and promoting wound healing. And HSP90 also plays an important role in the occurrence and progression of tumors. In recent years, HSP90 inhibitors have made some achievements in molecular targeted therapy for malignant tumors, but further research is needed in clinical application. In this paper, the research status of the relationship between hepatocellular carcinoma targeted by heat shock protein 90 was reviewed.
An efficient procedure for purification of recombinant human β heat shock protein 90
M Bandehpour,M Khodabandeh,N Mostaffa,Z Sharifnia
DARU : Journal of Pharmaceutical Sciences , 2010,
Abstract: "nBackground and the purpose of the study: Heat Shock Protein 90 (Hsp90) is typically the most abundant chaperone in the eukaryotic cell cytoplasm, and its expression is essential for loading immunogenic peptides onto major histocompatibility complex molecules for presentation to T-cells. Therefore, it may act as a good candidate as an adjuvant molecule in vaccine technology. "n Methods: Initially the human Hsp90β gene was cloned into the heat inducible expression vector pGP1-2 and then the recombinant protein was isolated by ion exchange chromatography. After intradermal injection of confirmed purified band of protein to rabbits and isolation of the serum IgG antibody, for its affinity purification, the rabbit’s purified Hsp90 specific IgG was coupled to the cyanogen bromide-activated Sepharose 4B. Results: The recovery of the purified protein of interest by affinity chromatography was 50% . "n "nConclusion: This research enabled purification of human heat shock protein by a laboratory "n "nprepared column chromatography. "n
Functional Characterization of the Small Heat Shock Protein Hsp12p from Candida albicans  [PDF]
Man-Shun Fu, Luisa De Sordi, Fritz A. Mühlschlegel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042894
Abstract: Hsp12p is considered to be a small heat shock protein and conserved among fungal species. To investigate the expression of this heat shock protein in the fungal pathogen Candida albicans we developed an anti-CaHsp12p antibody. We show that this protein is induced during stationary phase growth and under stress conditions including heat shock, osmotic, oxidative and heavy metal stress. Furthermore, we find that CaHsp12p expression is influenced by the quorum sensing molecule farnesol, the change of CO2 concentration and pH. Notably we show that the key transcription factor Efg1p acts as a positive regulator of CaHsp12p in response to heat shock and oxidative stress and demonstrate that CaHsp12p expression is additionally modulated by Hog1p and the cAMP-PKA signaling pathway. To study the function of Hsp12p in C. albicans we generated a null mutant, in which all four CaHSP12 genes have been deleted. Phenotypic analysis of the strain shows that CaHSP12 is not essential for stress resistance, morphogenesis or virulence when tested in a Drosophila model of infection. However, when overexpressed, CaHSP12 significantly enhanced cell-cell adhesion, germ tube formation and susceptibility to azole antifungal agents whilst desensitizing C. albicans to the quorum sensing molecule farnesol.
Heat Shock Protein 90 in Plants: Molecular Mechanisms and Roles in Stress Responses  [PDF]
Zhao-Shi Xu,Zhi-Yong Li,Yang Chen,Ming Chen,Lian-Cheng Li,You-Zhi Ma
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131215706
Abstract: The heat shock protein 90 (Hsp90) family mediates stress signal transduction, and plays important roles in the control of normal growth of human cells and in promoting development of tumor cells. Hsp90s have become a currently important subject in cellular immunity, signal transduction, and anti-cancer research. Studies on the physiological functions of Hsp90s began much later in plants than in animals and fungi. Significant progress has been made in understanding complex mechanisms of HSP90s in plants, including ATPase-coupled conformational changes and interactions with cochaperone proteins. A wide range of signaling proteins interact with HSP90s. Recent studies revealed that plant Hsp90s are important in plant development, environmental stress response, and disease and pest resistance. In this study, the plant HSP90 family was classified into three clusters on the basis of phylogenetic relationships, gene structure, and biological functions. We discuss the molecular functions of Hsp90s, and systematically review recent progress of Hsp90 research in plants.
LPS-Induced Delayed Preconditioning Is Mediated by Hsp90 and Involves the Heat Shock Response in Mouse Kidney  [PDF]
Tamás Kaucsár, Csaba Bodor, Mária Godó, Csaba Szalay, Csaba Révész, Zalán Németh, Miklós Mózes, Gábor Szénási, László Rosivall, Csaba S?ti, Péter Hamar
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092004
Abstract: Introduction We and others demonstrated previously that preconditioning with endotoxin (LPS) protected from a subsequent lethal LPS challenge or from renal ischemia-reperfusion injury (IRI). LPS is effective in evoking the heat shock response, an ancient and essential cellular defense mechanism, which plays a role in resistance to, and recovery from diseases. Here, by using the pharmacological Hsp90 inhibitor novobiocin (NB), we investigated the role of Hsp90 and the heat shock response in LPS-induced delayed renal preconditioning. Methods Male C57BL/6 mice were treated with preconditioning (P: 2 mg/kg, ip.) and subsequent lethal (L: 10 mg/kg, ip.) doses of LPS alone or in combination with NB (100 mg/kg, ip.). Controls received saline (C) or NB. Results Preconditioning LPS conferred protection from a subsequent lethal LPS treatment. Importantly, the protective effect of LPS preconditioning was completely abolished by a concomitant treatment with NB. LPS induced a marked heat shock protein increase as demonstrated by Western blots of Hsp70 and Hsp90. NB alone also stimulated Hsp70 and Hsp90 mRNA but not protein expression. However, Hsp70 and Hsp90 protein induction in LPS-treated mice was abolished by a concomitant NB treatment, demonstrating a NB-induced impairment of the heat shock response to LPS preconditioning. Conclusion LPS-induced heat shock protein induction and tolerance to a subsequent lethal LPS treatment was prevented by the Hsp90 inhibitor, novobiocin. Our findings demonstrate a critical role of Hsp90 in LPS signaling, and a potential involvement of the heat shock response in LPS-induced preconditioning.
Targeting Heat Shock Protein 90 for the Treatment of Malignant Pheochromocytoma  [PDF]
Alessio Giubellino, Carole Sourbier, Min-Jung Lee, Brad Scroggins, Petra Bullova, Michael Landau, Weiwen Ying, Len Neckers, Jane B. Trepel, Karel Pacak
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056083
Abstract: Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma.
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