Topic
Heat shock protein
About: Heat shock protein is a research topic. Over the lifetime, 20701 publications have been published within this topic receiving 1040593 citations. The topic is also known as: Heat-Shock Proteins & heat shock protein.
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TL;DR: Testing the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin in simian cells shows that malfoldingper se, rather than abnormal glycosylation1, is the proximal inducer of this family of stress proteins.
Abstract: Two glucose-regulated proteins, GRP78 and GRP94, are major constituents of the endoplasmic reticulum (ER) of mammalian cells. These proteins are synthesized constitutively in detectable amounts under normal growth conditions; they can also be induced under a variety of conditions of stress including glucose starvation and treatment with drugs that inhibit cellular glycosylation, with calcium ionophores or with amino-acid analogues. Unlike the closely-related heat shock protein (HSP) family, the GRPs are not induced significantly by high temperature. Recently, GRP78 has been identified as the immunoglobulin heavy chain binding protein (BiP) (ref. 5 and Y.K. et al., in preparation) which binds transiently to a variety of nascent, wild-type secretory and transmembrane proteins and permanently to malfolded proteins that accumulate within the ER. We have tested the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin (HA) in simian cells. Only malfolded HAs, whose transport from the ER is blocked, induced the synthesis of GRPs 78 and 94. Additional evidence is presented that malfolding per se, rather than abnormal glycosylation, is the proximal inducer of this family of stress proteins.
1,245 citations
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TL;DR: The results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.
Abstract: 5628 Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins including HER-2, Akt, Raf-1, Bcr-Abl, and mutated p53. The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) binds Hsp90 and induces proteasomal degradation of Hsp90 ‘client’ proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells, and 17-AAG is currently in Phase I clinical trials. However, the molecular basis of the tumor selectivity of Hsp90 inhibitors is unknown. The selective retention of 17-AAG in subcutaneous tumor masses in vivo suggests the existence of a drug ‘sink’ in tumor cells. Here we report that Hsp90 derived from tumor cells and clinical cancer biopsies has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells and tissues. Furthermore, the cytotoxic activity of 17-AAG correlates closely with the binding affinity of the drug to Hsp90 isolated from different cells. This binding affinity change is induced by association of Hsp90 with it’s co-chaperone proteins since tumor Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. Additional experiments addressing the relative contribution of cell cycling, oncoprotein overexpression and stress to the activation of Hsp90 will also be presented. We propose a model of Hsp90-dependent malignant progression in which, as tumor cells gradually accumulate mutant and overexpressed signaling proteins, Hsp90 becomes engaged in active chaperoning and stabilization of oncoproteins, and adopts a novel high-affinity form induced by bound co-chaperone proteins. Interestingly, dependence on the activated, high affinity chaperone could make Hsp90 an ’Achilles heel’ of tumor cells, driving the selective accumulation and bioactivity of pharmacological Hsp90 inhibitors, and making tumor Hsp90 a unique cancer target.
1,225 citations
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TL;DR: Analysis of HSF cDNA clones from many species has defined structural and regulatory regions responsible for the inducible activities of the conserved heat shock transcription factor.
Abstract: Organisms respond to elevated temperatures and to chemical and physiological stresses by an increase in the synthesis of heat shock proteins. The regulation of heat shock gene expression in eukaryotes is mediated by the conserved heat shock transcription factor (HSF). HSF is present in a latent state under normal conditions; it is activated upon heat stress by induction of trimerization and high-affinity binding to DNA and by exposure of domains for transcriptional activity. Analysis of HSF cDNA clones from many species has defined structural and regulatory regions responsible for the inducible activities. The heat stress signal is thought to be transduced to HSF by changes in the physical environment, in the activity of HSF-modifying enzymes, or by changes in the intracellular level of heat shock proteins.
1,215 citations
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TL;DR: A yeast cytosol is shown to contain two distinct activities that stimulate protein translocation across microsomal membranes that increase the rate of translocation.
Abstract: A yeast cytosol is shown to contain two distinct activities that stimulate protein translocation across microsomal membranes. One activity was purified. It consists of two constitutively expressed 70K heat shock related proteins that increase the rate of translocation. Possible mechanisms of action of these proteins are discussed.
1,208 citations
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TL;DR: These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing.
Abstract: Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing.
1,204 citations