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PubMed1996

Induction and Regulation of Heat-Shock Gene Expression by an Amino Acid Analog in Soybean Seedlings.

The effect of the proline analog azetidine-2-carboxylic acid (Aze) on the induction and the regulation of heat-shock (HS) mRNA accumulation and heat-shock protein (HSP) synthesis in soybean (Glycine max) seedlings was studied. Treatment with Aze elicited an HS-like response at the normal growth temperature, 28[deg]C, with seven of nine HS cDNA clones tested. Two cDNA clones, Gm-Hsp22.5 and pFS2033, share 78% identity; however, transcripts hybridizing to GmHsp22.5 but not pFS2033 accumulated with Aze treatment at 28[deg]C. Substantial incorporation of radioactive amino acid into high molecular weight HSPs but not low molecular weight HSPs was observed in vivo during Aze treatment at 28[deg]C. Low molecular weight HSPs were detected using antibodies raised against an abundant member of low molecular weight class I HSPs, indicating that low molecular weight HSPs were synthesized at normal growth temperatures during Aze treatment despite a lack of substantial in vivo radioactive amino acid incorporation. In summary, Aze treatment induced accumulation of most but not all HS mRNAs and HSPs in soybean seedlings; the observations presented here suggest differential regulation among various HS genes at the transcriptional and posttranscriptional levels.

Journal Article↗

PubMed1984

Synthesis, modification and structural binding of heat-shock proteins in tomato cell cultures.

Synthesis of about 30 acidic and 18 basic heat-shock proteins (hsps) is induced in suspension cultures of tomato (Lycopersicon peruvianum) if subjected to supraoptimal temperature conditions (35-40 degrees C). A characteristic aspect of the plant heat-shock response is the formation of cytoplasmic granular aggregates, heat-shock granules, containing distinct heat-shock proteins as major structural components and, in addition, several hitherto undetected minor acidic and basic heat-shock proteins. Structural binding of heat-shock proteins, i.e. assembly of heat-shock granules, is dependent on the persistance of supraoptimal temperature conditions. Despite the ongoing synthesis also at 25 degrees C, e.g. in pulse heat-shocked cultures, these proteins are accumulated exclusively in soluble form. Individual heat-shock proteins are characterized by their kinetics of synthesis and are classified by their compartmentation behaviour into class A proteins (exclusively found in soluble form, e.g. hsps 95 and 80), class B proteins (5-10% bound to heat-shock granules, e.g. hsps 70, 68), class C proteins (30-80% bound to heat-shock granules, e.g. hsps 21, 17, 15) and class D proteins, which are minor heat-shock proteins only detected in structure-bound form. Major representatives are modified proteins, i.e. hsps 95, 80, 70 and 68 are phosphorylated and hsps 80, 74, 70 and 17 are methylated proteins (numbers 70, 80 etc. refer to 10(-3) Mr). Under heat-shock conditions synthesis of the proteins detected in control cells (25 degrees C proteins) exhibits two patterns. There are proteins with continued and proteins with discontinued synthesis. Synthesis of most of the latter proteins is resumed very rapidly after shift-down to 25 degrees C, even in the presence of actinomycin D. We conclude that reversible segregation of distinct mRNA species from the translation apparatus contributes to the heat-shock-specific pattern of protein synthesis in plants also.

Autoradiography↗

PubMed1998

Heat shock proteins and the inflammatory response.

The heat shock proteins (HSPs) are important in the cellular response to stress and in cellular homeostatic functions such as protein synthesis and protein transport across membranes. An emerging body of data supports a role for HSPs in the inflammatory response, suggesting that HSPs participate in cytokine signal transduction and in the control of cytokine gene expression, that HSPs enhance antigen presentation to T lymphocytes, and that HSPs displayed on the surface of cells are important in targeting cytotoxic cells. Because changes in HSP accumulation occur in the whole organism under physiologic conditions, understanding the role of HSPs in the immune/inflammatory response may aid in understanding the organism's response to danger.

Adaptation, Physiological↗

PubMed2005

Exposure to mycobacteria primes the immune system for evolutionarily diverse heat shock proteins.

During stress conditions, such as infection, the synthesis of heat shock proteins (HSPs) in microorganisms is upregulated. Since a high degree of homology exists within each HSP family, we postulated that exposure to microorganisms could prime the immune system for evolutionarily diverse HSPs. We tested this hypothesis by priming mice with three microorganisms, namely, Mycobacterium bovis BCG, Mycobacterium vaccae, and Chlamydia pneumoniae. After this, mice received a dose of the various HSPs. We found that BCG and M. vaccae but not C. pneumoniae primed the immune system for the induction of secondary immunoglobulin G (IgG) responses to most of the HSPs tested. Analysis of the IgG1 and IgG2a profile and gamma interferon production induced against the HSPs revealed the induction of a mixture of responses. We also observed that sera from mice treated with M. vaccae and HSP70 were cross-reactive, but no antibody complexes were observed in their kidneys, which frequently are targets for autoantibody reactions. Our findings add further support for the use of HSPs as effective vaccine adjuvants.

Animals↗

PubMed1991

Lysis of Escherichia coli by beta-lactams which bind penicillin-binding proteins 1a and 1b: inhibition by heat shock proteins.

The heat shock proteins (HSPs) of Escherichia coli were artificially induced in cells containing the wild-type rpoH+ gene under control of a tac promoter. At 30 degrees C, expression of HSPs produced cells that were resistant to lysis by cephaloridine and cefsulodin, antibiotics that bind penicillin-binding proteins (PBPs) 1a and 1b. This resistance could be reversed by the simultaneous addition of mecillinam, a beta-lactam that binds PBP 2. However, even in the presence of mecillinam, cells induced to produce HSPs were resistant to lysis by ampicillin, which binds all the major PBPs. Lysis of cells induced to produce HSPs could also be effected by imipenem, a beta-lactam known to lyse nongrowing cells. These effects suggest the existence of at least two pathways for beta-lactam-dependent lysis, one inhibited by HSPs and one not. HSP-mediated lysis resistance was abolished by a mutation in any one of five heat shock genes (dnaK, dnaJ, grpE, GroES, or groEL). Thus, resistance appeared to depend on the expression of the complete heat shock response rather than on any single HSP. Resistance to lysis was significant in the absence of the RelA protein, implying that resistance could not be explained by activation of the stringent response. Since many environmental stresses promote the expression of HSPs, it is possible that their presence contributes an additional mechanism toward development in bacteria of phenotypic tolerance to beta-lactam antibiotics.

Anti-Bacterial Agents↗

PubMed1989

The major low-molecular-weight heat shock protein in chloroplasts shows antigenic conservation among diverse higher plant species.

Several plant species are known to synthesize low-molecular-weight nucleus-encoded heat shock proteins (HSPs) which localize to chloroplasts. DNA sequence analysis of chloroplast HSP cDNAs from pea (Pisum sativum) and soybean (Glycine max) has shown that the carboxyl-terminal halves of these proteins are homologous to low-molecular-weight HSPs from a wide range of eucaryotes (E. Vierling, R. T. Nagao, A. E. DeRocher, and L. M. Harris, EMBO J. 7:575-581, 1988). We used a pea cDNA to construct fusion proteins containing either the carboxyl-terminal heat shock domain or the amino-terminal domain of the chloroplast HSP. The fusion proteins were overexpressed in Escherichia coli and used to produce choloroplast HSP-specific polyclonal antibodies. The carboxyl-terminal antibodies recognized chloroplast HSP precursor proteins from pea and from three divergent plant species, Arabidopsis thaliana, petunia (Petunia hybrida), and maize (Zea mays). The amino-terminal antibodies recognized effectively only the pea precursor. When intact plants of each species were subjected to a heat stress regime mimicking field growth conditions, significant levels of the mature forms of the chloroplast HSPs accumulated in pea, A. thaliana, and maize. The levels of accumulated HSPs remained unchanged for 12 h following the stress treatment. We conclude that the synthesis of chloroplast-localized HSPs is an important component of the stree response in all higher plants and that chloroplast HSPs from dicotyledonous and monocotyledonous plants have a conserved carboxyl-terminal domain.

Antigens↗

PubMed2006

Targeting heat shock response to sensitize cancer cells to proteasome and Hsp90 inhibitors.

Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression of such induction may sensitize cancer cells to these drugs. Here, we knocked out the major heat shock transcription factor HSF-1 in several cancer cell lines using small interfering RNA and showed that such cells, which can no longer induce Hsps in response to proteasome and Hsp90 inhibitors, become more sensitive to these drugs. Furthermore, we developed a high-throughput screen for small molecules that inhibit induction of Hsps. The first step was a cell-based screen for inhibitors of Hsps-mediated luciferase refolding followed by a counterscreen for toxicity. The second step was a direct testing for inhibition of Hsp induction by immunoblotting with anti-Hsp72 antibody. After screening of 20,000 compounds from several diversity libraries, we focused on a compound we called NZ28, which potently inhibited induction of Hsps by heat shock, proteasome, and Hsp90 inhibitors in a variety of cell lines, and showed no significant toxicity. After testing of a set of analogues of NZ28, we identified a structural element that was critical for the activity. We also identified another inhibitor of the Hsp induction that was practically nontoxic. This compound, which we called emunin, strongly sensitized myeloma cells to proteasome and Hsp90 inhibitors and prostate carcinoma cells to proteasome inhibitors. This work indicates that targeting the heat shock response may facilitate use of proteasome and Hsp90 inhibitors for cancer treatment.

Animals↗

PubMed2005

Heat shock proteins in renal cell carcinomas.

Renal cell carcinoma (RCC) represents one of the most common cancer types in the Western World. One third of the RCC patients had metastasis at presentation with a poor 5-year survival. Nephrectomy is the most important treatment modality of this disease, since most of the RCCs are resistant to cytotoxic chemotherapy and radiation therapy. Recent immunotherapeutic approaches have been shown to improve the survival rate of RCC patients. Thus, RCC appears to have an immunogenic basis, and therefore represents an attractive target for immunotherapies. So far, only a few RCC-associated antigens have been characterized. However, with the implementation of ome-based technologies, an increasing number of tumor-associated antigens and tumor markers has been identified that includes various heat shock proteins (HSPs). RCC lesions demonstrate heterogeneous expression patterns for HSPs. In most cases overexpression of certain HSPs, such as HSP27, HSP70 and HSP72, has been detected both in RCC cell lines as well as in the tumor lesions when compared to normal kidney epithelium. Furthermore, HSPs play an important role in apoptotic cell death, in the regulation of cell proliferation and in the augmentation of lysis of RCC by HLA class I-restricted cytotoxic T lymphocytes. In this context, it is noteworthy that wild-type and mutated HSPs have been identified to act as tumor-associated antigens, which consequently resulted in the first clinical phase I and II trials using HSP for vaccination of RCC patients. In this chapter we will briefly present the relevance of HSPs in the pathomechanisms of RCC.

Biomarkers, Tumor↗

PubMed1991

Heat shock proteins and systemic lupus erythematosus.

This review briefly defines the heat shock proteins (hsps), their classification and their functions. The hypothesis that links hsps to the development of autoimmunity is explored, together with the rationale for investigation of the relationship between hsps and systemic lupus erythematosus (SLE). Thus, published work on this subject falls into three main categories: the overexpression of hsps in SLE, the development of autoantibodies to hsps in SLE, and the surface expression of hsps in peripheral blood mononuclear cells in SLE. This work is reviewed in detail. In conclusion, we describe areas for further study and outline ways in which this is being approached.

Autoimmunity↗

PubMed1989

The developmental expression of the heat-shock response in Xenopus laevis.

We have investigated the Xenopus heat-shock response of somatic cells, oocytes and embryos. Xenopus defolliculated oocytes displayed a highly variable response to heat shock depending on the culture medium. Intact follicles, however, respond to heat stress by synthesizing an invariant pattern of hsps. Although a subset of the hsp70/68 complex is expressed constitutively in the absence of heat shock in oocytes and embryos (hsc70), actual induction of hsps in response to stress does not occur until the blastula stage when transcription of the zygotic genome is first activated. By gastrulation, the hsps of somatic cells, including members of the hsp30/26 complex, were expressed coordinately in response to heat shock. We further show that Xenopus hsps have different solubilities perhaps reflecting their different subcellular locations. The 26,000-30,000 Mr complex (hsp30/26) was present almost exclusively in a detergent-insoluble fraction, as was 25-50% of the hsp70/68 complex and greater than 50% of hsp56, suggesting that these hsps may be associated with the cytoskeleton during a heat shock. In contrast, the other Xenopus hsps (hsp86, hsp75 and hsp61) were totally solubilized in a low-salt buffer.

Animals↗

PubMed2004

"The stress of dying": the role of heat shock proteins in the regulation of apoptosis.

Heat shock proteins (Hsps) are a family of highly homologous chaperone proteins that are induced in response to environmental, physical and chemical stresses and that limit the consequences of damage and facilitate cellular recovery. The underlying ability of Hsps to maintain cell survival correlates with an inhibition of caspase activation and apoptosis that can, but does not always, depend upon their chaperoning activities. Several mechanisms proposed to account for these observations impact on both the "intrinsic", mitochondria-dependent and the "extrinsic", death-receptor-mediated pathways to apoptosis. Hsps can inhibit the activity of pro-apoptotic Bcl-2 proteins to prevent permeabilization of the outer mitochondrial membrane and release of apoptogenic factors. The disruption of apoptosome formation represents another mechanism by which Hsps can prevent caspase activation and induction of apoptosis. Several signaling cascades involved in the regulation of key elements within the apoptotic cascade are also subject to modulation by Hsps, including those involving JNK, NF-kappaB and AKT. The coordinated activities of the Hsps thus modulate multiple events within apoptotic pathways to help sustain cell survival following damaging stimuli.

Animals↗

PubMed1990

Developmental expression of Drosophila melanogaster small heat-shock proteins.

We have investigated the developmental expression of the small heat-shock proteins (hsps) during embryogenesis and in adult flies by immunocytology using an antibody that specifically identifies the small hsps. Antibody staining of unstressed early embryos reveals a predominantly cytoplasmic, homogeneous distribution of the small hsps throughout the embryo. At 6h of development small hsp expression can be identified in large, neuroblast-like cells within the extended germ band and in the brain of the embryo. During germ band contraction these cells appear to migrate to the midline where they align pairwise in a segmental pattern. After germ band contraction is complete a high level of small hsp expression can be observed in the midline glia (MECs) and in a cluster of six non-neuronal cells within the midline. In contrast to several other genes that are known to be important for embryogenesis and are expressed in the central nervous system (CNS) of embryos, CNS-specific expression of the small hsps is not restricted to the embryo but is also observed in the adult fly. In adult flies strong small hsp expression is observed in the brain, the thoracic ganglion and the leg nerves. Since the small hsps seem to be expressed predominantly in the glia of the nervous system, our data suggest a protective or stabilizing function of the small hsps within the nervous system during normal fly development, which is independent of the stress response.

Animals↗

PubMed2004

Paeoniflorin, a novel heat shock protein-inducing compound.

Heat shock proteins (HSPs) are induced by various physical, chemical, and biological stresses. HSPs are known to function as molecular chaperones, and they not only regulate various processes of protein biogenesis but also function as lifeguards against proteotoxic stresses. Because it is very useful to discover nontoxic chaperone-inducing compounds, we searched for them in herbal medicines. Some herbal medicines had positive effects on the induction of HSPs (Hsp70, Hsp40, and Hsp27) in cultured mammalian cells. We next examined 2 major constituents of these herbal medicines, glycyrrhizin and paeoniflorin, with previously defined chemical structures. Glycyrrhizin had an enhancing effect on the HSP induction by heat shock but could not induce HSPs by itself. In contrast, paeoniflorin had not only an enhancing effect but also an inducing effect by itself on HSP expression. Thus, paeoniflorin might be termed a chaperone inducer and glycyrrhizin a chaperone coinducer. Treatment of cells with paeoniflorin but not glycyrrhizin resulted in enhanced phosphorylation and acquisition of the deoxyribonucleic acid-binding ability of heat shock transcription factor 1 (HSF1), as well as the formation of characteristic HSF1 granules in the nucleus, suggesting that the induction of HSPs by paeoniflorin is mediated by the activation of HSF1. Also, thermotolerance was induced by treatment with paeoniflorin but not glycyrrhizin. Paeoniflorin had no toxic effect at concentrations as high as 80 microg/ mL (166.4 microM). To our knowledge, this is the first report on the induction of HSPs by herbal medicines.

Animals↗

PubMed2001

The role of heat shock proteins and their receptors in the activation of the immune system.

Heat shock proteins (HSPs) have been described as potent tumor vaccines in animal models and are currently studied in clinical trials. The underlying immune response relies on immunogenic peptides that the HSPs have acquired intracellularly by interfering with the classical antigen processing pathways. There have been numerous reports shedding light on how HSPs are able to gain this function and a number of important requirements for HSP-mediated specific immunity have been described: first, the ability of HSPs to bind immunogenic peptides. Second, the acquisition of HSPs by specialized antigen presenting cells with efficient antigen processing pathways capable of inducing cellular immune responses. Third, the existence of specific receptors on the surfaces of antigen presenting cells, allowing efficient and rapid uptake of HSP-peptide complexes from the extracellular fluid. And fourth, the ability of heat shock proteins to activate antigen presenting cells, enabling the latter to prime cytotoxic T cell responses against the peptides associated to HSPs.

Animals↗

PubMed2001

Changes in skeletal muscle heat shock proteins: pathological significance.

In response to stress, cells rapidly produce a series of new proteins known as heat shock proteins (HSP). HSPs are considered to be molecular chaperones which play a universal role in maintaining cellular homeostasis. It is known that different HSPs are expressed in skeletal muscle, namely, small HSPs (including ubiquitin, alpha B- crystallin, HSP20 and HSP 27), HSP70, HSP60 and HSP90. Skeletal muscle is a complex and heterogeneous system in that its contractile proteins are made of different isoforms to form various muscle fibre types, and each type of muscle fibre has its own histochemical and functional characteristics. It seems that the induction of HSPs differs with muscle fibre type suggesting HSP expression is muscle fibre type specific. HSPs have been shown to respond in muscle diseases and following exercise. However, the molecular mechanisms of HSP induction, regulation and its role in maintaining the muscle function, are not completely understood. Relatively few studies of HSP have been conducted in human skeletal muscles. This review discusses the significance of changes of HSPs in skeletal muscle in both physiological and pathological conditions.

Animals↗

PubMed1992

Emerging role of heat shock proteins in biology and medicine.

All cells, procaryotic and eucaryotic, respond to an elevation in temperature by increasing the synthesis of a family of proteins collectively known as heat shock proteins (HSPs). HSPs are among the most highly conserved and abundant proteins in nature. Studies on the regulation of the synthesis of HSPs have for several years shed light on the mechanisms regulating gene expression. The results from recent years, showing that HSPs play crucial roles in a wide variety of normal cellular processes, has made them an object of even broader interest, first to molecular and cellular biologists and later to specialists in various fields of medicine including oncology, immunology, infectious disease, autoimmunity, embryology, neurology and endocrinology. The aim of this review is to briefly summarize our present knowledge of the regulation of the heat shock response and the structure of the relevant gene products, HSPs. Moreover, some of the exciting associations between HSPs and various fields of medicine will be discussed.

Animals↗

PubMed2004

Bacterial heat shock proteins promote CD91-dependent class I MHC cross-presentation of chaperoned peptide to CD8+ T cells by cytosolic mechanisms in dendritic cells versus vacuolar mechanisms in macrophages.

APCs process mammalian heat shock protein (HSP):peptide complexes to present HSP-chaperoned peptides on class I MHC (MHC-I) molecules to CD8(+) T cells. HSPs are also expressed in prokaryotes and chaperone microbial peptides, but the ability of prokaryotic HSPs to contribute chaperoned peptides for Ag presentation is unknown. Our studies revealed that exogenous bacterial HSPs (Escherichia coli DnaK and Mycobacterium tuberculosis HSP70) delivered an extended OVA peptide for processing and MHC-I presentation by both murine macrophages and dendritic cells. HSP-enhanced MHC-I peptide presentation occurred only if peptide was complexed to the prokaryotic HSP and was dependent on CD91, establishing CD91 as a receptor for prokaryotic as well as mammalian HSPs. Inhibition of cytosolic processing mechanisms (e.g., by transporter for Ag presentation deficiency or brefeldin A) blocked HSP-enhanced peptide presentation in dendritic cells but not macrophages. Thus, prokaryotic HSPs deliver chaperoned peptide for alternate MHC-I Ag processing and cross-presentation via cytosolic mechanisms in dendritic cells and vacuolar mechanisms in macrophages. Prokaryotic HSPs are a potential source of microbial peptide Ags during phagocytic processing of bacteria during infection and could potentially be incorporated in vaccines to enhance presentation of peptides to CD8(+) T cells.

Adjuvants, Immunologic↗

PubMed2004

Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells.

APCs process heat shock protein (HSP):peptide complexes to present HSP-chaperoned peptides on class I MHC molecules, but the ability of HSPs to contribute chaperoned peptides for class II MHC (MHC-II) Ag processing and presentation is unclear. Our studies revealed that exogenous bacterial HSPs (Escherichia coli DnaK and Mycobacterium tuberculosis HSP70) delivered an extended OVA peptide for processing and MHC-II presentation, as detected by T hybridoma cells. Bacterial HSPs enhanced MHC-II presentation only if peptide was complexed to the HSP, suggesting that the key HSP function was enhanced delivery or processing of chaperoned peptide Ag rather than generalized enhancement of APC function. HSP-enhanced processing was intact in MyD88 knockout cells, which lack most TLR signaling, further suggesting the effect was not due to TLR-induced induction of accessory molecules. Bacterial HSPs enhanced uptake of peptide, which may contribute to increased MHC-II presentation. In addition, HSPs enhanced binding of peptide to MHC-II molecules at pH 5.0 (the pH of vacuolar compartments), but not at pH 7.4, indicating another mechanism for enhancement of MHC-II Ag processing. Bacterial HSPs are a potential source of microbial peptide Ags during phagocytic processing of bacteria during infection and could potentially be incorporated in vaccines to enhance presentation of peptides to CD4+ T cells.

Amino Acid Sequence↗