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At least 19 recordsLinked to original sources

PubMed1996

Distinctive immunohistochemical profiles of small heat shock proteins (heat shock protein 27 and alpha B-crystallin) in human brain tumors.

BACKGROUND: Recent studies have described alpha B-crystallin as a member of the small heat shock protein (HSP) family, and the expressions of alpha-crystallin-related small heat shock proteins, namely HSP27 and alpha B-crystallin, in the brain appear to be regulated in a similar way by various stress conditions. METHODS: A comparative immunohistochemical analysis was performed on 198 human brain tumors to examine the expressions of HSP27 and alpha B-crystallin. RESULTS: Positive staining with HSP27 was frequently observed in schwannomas, craniopharyngiomas, epidermoid cysts, and metastatic tumors to the brain. The immunopositivity of HSP27 was relatively low in tumors originating from neuroepithelium as well as in meningiomas; however, a statistically significantly higher percentage of HSP27-positive cells was noted in their anaplastic counterparts, such as glioblastomas, anaplastic oligodendrogliomas, anaplastic ependymomas, and anaplastic meningiomas (P < 0.005). Conversely, a positive immunoexpression of alpha B-crystallin was frequently observed among astrocytic tumors, schwannomas, hemangioblastomas, and chordomas. CONCLUSIONS: The immunohistochemical expression of HSP27 and alpha B-crystallin differed among histologic types of tumors. Furthermore, the immunopositivity of HSP27, which was considered to play a role not only in drug resistance but also in the regulation of cell proliferation, increased in proportion to the anaplasia of the tumors.

Astrocytoma↗

PubMed2002

Circulating heat shock protein and heat shock protein antibody levels in established hypertension.

OBJECTIVE: Serum Hsp60 and anti-Hsp65 antibody levels are raised in subjects with borderline hypertension, and there is an association between circulating Hsp60 levels and early atherosclerosis. Given the recognized relationship between hypertension and atherosclerosis, this study determined heat shock protein and heat shock protein antibody levels in subjects with established hypertension. METHODS: Samples from 111 men with hypertension were obtained from the European Lacidipine study on Atherosclerosis and samples from 75 normotensive controls were taken from a population-screening programme (diastolic pressure, 95 and 80 mmHg, respectively). Hsp60, Hsp70 and anti-human Hsp60, anti-human Hsp70 and anti-mycobacterial Hsp65 antibody levels were measured by enzyme immunoassay. Intima-media thickness (I-M) and the presence of carotid atherosclerosis were determined by ultrasonography. RESULTS: Hsp60, Hsp70 and anti-Hsp60 antibody levels in hypertension were similar to those in normotensive controls, whereas anti-Hsp70 and anti-Hsp65 antibody levels were elevated ( 0.001). Hsp60 levels and atherosclerosis were not associated. Anti-Hsp70 and anti-Hsp65 antibody levels were both associated with hypertension, independently of age, smoking habits and blood lipids. CONCLUSIONS: This study demonstrates elevated levels of selected heat shock protein antibodies in subjects with hypertension. Although the association between heat shock protein antibody levels and human cardiovascular stress/disease appears to be robust, the relationship of the latter with heat shock protein levels is more complex. Further studies are required before the factors inducing, and the clinical significance of, circulating heat shock proteins can be evaluated.

Antibodies↗

PubMed2002

Chaperoning signaling pathways: molecular chaperones as stress-sensing 'heat shock' proteins.

Heat shock proteins interact with multiple key components of signaling pathways that regulate growth and development. The molecular relationships between heat shock proteins, various signaling proteins and partner proteins appear to be critical for the normal function of signal transduction pathways. The relative levels of these proteins may be important, as too little or too much Hsp70 or Hsp90 can result in aberrant growth control, developmental malformations and cell death. Although the functions of heat shock proteins as molecular chaperones have been well characterized, their complementary role as a 'stress-induced' proteins to monitor changes and alter the biochemical environment of the cell remains elusive. Genetic and molecular interactions between heat shock proteins, their co-chaperones and components of signaling pathways suggest that crosstalk between these proteins can regulate proliferation and development by preventing or enhancing cell growth and cell death as the levels of heat shock proteins vary in response to environmental stress or disease.

Cell Differentiation↗

PubMed1993

[Temperature modification of the mutation process and heat shock proteins].

Heat shock protein synthesis and mutagenesis (X-chromosome losses induced by radiation and high temperature) were studied in different. Drosophila melanogaster strains. Two models (strain l(1)ts403 with the defect in heat shock protein synthesis and the heat-resistant T strain with a specific reaction to the extreme temperature differing from the wild type strains) were used. The correlation between heat shock protein synthesis and the effect of synergism in the action of radiation and heat shock was revealed. It was concluded that HSPs are one of the components in mutagenic processes.

Animals↗

PubMed2001

Activation of the herpes simplex virus type-1 origin-binding protein (UL9) by heat shock proteins.

Heat shock proteins participate in the initiation of DNA replication of different organisms by facilitating the assembly of initiation complexes. We have examined the effects of human heat shock proteins (Hsp40 and Hsp70) on the interaction of the herpes simplex virus type-1 initiator protein (UL9) with oriS, one of the viral origins of replication. Hsp40 and Hsp70 act substoichiometrically to increase the affinity of UL9 for oriS. The major contributor to this effect is Hsp40. Heat shock proteins also stimulate the ATPase activity of UL9 with oriS and increase opening of the origin. In contrast, heat shock proteins have no effect on the origin-independent activities of UL9 suggesting that their role is not merely in refolding denatured protein. These observations are consistent with a role for heat shock proteins in activating UL9 to efficiently initiate viral origin-dependent DNA replication. The action of heat shock proteins in this capacity is analogous to their role in activating the initiator proteins of other organisms.

Adenosine Triphosphatases↗

PubMed1995

HPV16 E7 oncoprotein induces expression of a 110 kDa heat shock protein.

Heat shock protein genes are induced by various kinds of stress. Besides stress, the heat shock family gene hsp70 has been shown to be induced by growth-stimulating agents such as the DNA virus oncoproteins and serum. Here, we report cloning of a novel cDNA that encodes a 100 kDa heat shock protein-related polypeptide as a human papillomavirus oncoprotein E7-inducible gene. E7 induces expression of this heat shock protein at the level of RNA synthesis. Moreover, the induction of this heat shock protein-mRNA was dependent on the conserved region 2 of the E7 protein, which is essential for binding to the proteins of the retinoblastoma family.

3T3 Cells↗

PubMed1998

Characterization of HDJ-2, a human 40 kD heat shock protein.

Heat shock proteins (HSP) are a large and complex family of proteins that play important roles in cellular function and survival. In previous studies, cDNA for a 45 kD human HSP (HDJ-2) was cloned and shown to be homologous to DNA-J, a bacterial HSP [F.M. Ausubel, R. Brent, R. E. Kingston, D.D. Moore, J.G. Seidman, J.A. Smith, K. Struhl, Current Protocols in Molecular Biology, John Wiley and Sons, New York, 1997; A. Chellaiah, A. Davis, T. Mohanakumar, Cloning of a unique human homologue of the Escherichia coli DNAJ heat shock protein, Biochim. Biophys. Acta 1174 (1993) 111-113]. We have also shown that the expression of HDJ-2 is highly elevated in kidney allograft biopsies of kidneys undergoing rejection [Y.G. Alevy, D. Brennan, S. Durriya, T. Howard, T. Mohanakumar, Increased expression of the HDJ-2 heat shock protein in biopsies of human rejected kidneys, Transplantation 61 (1996) 963-967]. Because of the potential importance of HDJ-2 to disease pathogenesis, we carried out studies to characterize the structure and regulation of HDJ-2. Polyclonal and monoclonal antibodies that recognize recombinant HDJ-2 were prepared and used to localize its cellular expression. HDJ-2 was found to be farnesylated but not glycosylated. This HSP was ubiquitously expressed in all of the cell types we analyzed and was localized throughout the cytoplasm and around the nuclear membrane. However, upon heat shock it migrated to the Golgi, nucleolus, and the nuclear membrane. Northern blot analysis revealed two mRNA transcripts whose synthesis was not affected by heat shock. In addition, Western blot analysis showed that expression of HDJ-2 was also not affected by heat shock. Thus, our study shows the characterization of a HSP which, because of its migration pattern upon heat shock, is an excellent candidate for a protein chaperon.

Animals↗

PubMed2001

Activation of heat shock transcription factor in yeast is not influenced by the levels of expression of heat shock proteins.

Heat shock transcription factor (HSF) transiently induces the expression of a universally conserved set of proteins, the heat shock proteins (Hsps), when cells are exposed to elevated temperatures as well as to a wide range of other environmental stresses. The tight control of heat shock gene expression has prompted a model, according to which HSF activity and 'free' heat shock protein levels are tied up in a regulatory loop. Other data have indicated that HSF senses stress directly. Here, we report that yeast cells in which the basal expression levels of Hsps have been significantly increased exhibit improved thermotolerance but display no detectable difference in the temperature required for transient activation of HSF. In a separate experiment, overexpression of SSA2, a member of the Hsp70 family and a prominent candidate for the feedback regulation of HSF, did not inhibit the heat shock response. Our findings challenge the dogma that relief of the suppression of HSF activity by Hsps can account for the acute heat shock response.

DNA-Binding Proteins↗

PubMed1996

Translational control during recovery from heat shock in the absence of heat shock proteins.

Heat shock results in a reduction in translational efficiency and an increase in mRNA stability in plants that is proportional to the severity of the stress. To determine whether the absence of heat shock proteins may affect the observed changes during translation or mRNA turnover, the effect that inhibiting transcription during a heat shock has on the subsequent translation of a reporter mRNA was examined. The presence of actinomycin D repressed heat shock protein synthesis in response to the application of a heat shock by more than 80%. The translational efficiency of the reporter mRNA was subject to a greater degree of repression following a heat shock when transcription was inhibited than it was in heat-shocked cells in which transcription was not inhibited. In contrast, inhibiting transcription during a heat shock did not prevent the heat-mediated increase in mRNA stability. These data suggest that ongoing transcription is needed during a heat shock to support a basal level of translational activity in the subsequent recovery from the stress but does not appear to be required for the heat-mediated increase in mRNA stability.

Animals↗

PubMed2005

Expression of heat shock proteins and heat shock protein messenger ribonucleic acid in human prostate carcinoma in vitro and in tumors in vivo.

Heat shock proteins (HSPs) are thought to play a role in the development of cancer and to modulate tumor response to cytotoxic therapy. In this study, we have examined the expression of hsf and HSP genes in normal human prostate epithelial cells and a range of prostate carcinoma cell lines derived from human tumors. We have observed elevated expressions of HSF1, HSP60, and HSP70 in the aggressively malignant cell lines PC-3, DU-145, and CA-HPV-10. Elevated HSP expression in cancer cell lines appeared to be regulated at the post-messenger ribonucleic acid (mRNA) levels, as indicated by gene chip microarray studies, which indicated little difference in heat shock factor (HSF) or HSP mRNA expression between the normal and malignant prostate cell lines. When we compared the expression patterns of constitutive HSP genes between PC-3 prostate carcinoma cells growing as monolayers in vitro and as tumor xenografts growing in nude mice in vivo, we found a marked reduction in expression of a wide spectrum of the HSPs in PC-3 tumors. This decreased HSP expression pattern in tumors may underlie the increased sensitivity to heat shock of PC-3 tumors. However, the induction by heat shock of HSP genes was not markedly altered by growth in the tumor microenvironment, and HSP40, HSP70, and HSP110 were expressed abundantly after stress in each growth condition. Our experiments indicate therefore that HSF and HSP levels are elevated in the more highly malignant prostate carcinoma cells and also show the dominant nature of the heat shock-induced gene expression, leading to abundant HSP induction in vitro or in vivo.

Animals↗

PubMed1992

Characterization and cellular distribution of human spermatozoal heat shock proteins.

Heat shock proteins (hsp) are ubiquitous components of all living systems. They are up-regulated in response to adverse changes in the cellular environment and at least one highly conserved group (hsp 70) is associated with the development of tolerance to various physico-chemical stress inducers. Spermatozoa have highly condensed chromatin and unlike somatic cells, are consequently unable to mount a stress response. However, using a combination of gel electrophoresis and immunoblotting with hsp-specific monoclonal antibodies, we report that proteins of M(r) 95 kDa and 70-75 kDa corresponding to hsp 90, and multiple forms of hsp 70 are present in human spermatozoa. Immunohistochemistry localized hsp 90 to the neck and tail of unfixed, acrosome-intact spermatozoa. In contrast, an equatorial ring surrounding the nucleus was observed in unfixed spermatozoa, acrosome-reacted with the calcium ionophore A23187. The ring was stained in cells fixed and permeabilized with ethanol, regardless of acrosomal status. Hsp 70 was an abundant surface antigen and as this protein was also abundant in seminal plasma, we believe that it may have been directly adsorbed onto the cell surface. More specific midpiece, equatorial and nuclear staining was also observed. Possible functions for spermatozoal heat shock proteins are discussed.

Antibodies, Monoclonal↗

PubMed2005

Heat shock protein 70, heat shock protein 32, and vascular endothelial growth factor production and their effects on lipopolysaccharide-induced apoptosis in porcine aortic endothelial cells.

Lipopolysaccharide (LPS) is a highly proactive molecule that causes in vivo a systemic inflammatory response syndrome and activates in vitro the inflammatory pathway in different cellular types, including endothelial cells (EC). Because the proinflammatory status could lead to EC injury and apoptosis, the expression of proinflammatory genes must be finely regulated through the induction of protective genes. This study aimed at determining whether an LPS exposure is effective in inducing apoptosis in primary cultures of porcine aortic endothelial cells and in stimulating heat shock protein (Hsp)70 and Hsp32 production as well as vascular endothelial growth factor (VEGF) secretion. Cells between third and eighth passage were exposed to 10 microg/mL LPS for 1, 7, 15, and 24 hours (time-course experiments) or to 1, 10, and 100 microg/mL LPS for 7 and 15 hours (dose-response experiments). Apoptosis was not affected by 1 microg/mL LPS but significantly increased in a dose-dependent manner with the highest LPS doses. Furthermore, apoptosis rate increased only till 15 hours of LPS exposure. LPS stimulated VEGF secretion in a dose-dependent manner; its effect became significant after 7 hours and reached a plateau after 15 hours. Both Hsp70 and Hsp32 expressions were induced by LPS in a dose-dependent manner after 7 hours. Subsequent studies were addressed to evaluate the protective role of Hsp32, Hsp70, and VEGF. Hemin, an Hsp32 inducer (5, 20, 50 microM), and recombinant VEGF (100 and 200 ng/mL), were added to the culture 2 hours before LPS (10 microg/mL for 24 hours); to induce Hsp70 expression, cells were heat shocked (42 degrees C for 1 hour) 15 hours before LPS (10 microg/mL for 24 hours). Hemin exposure upregulated Hsp32 expression in a dose-dependent manner and protected cells against LPS-induced apoptosis. Heat shock (HS) stimulated Hsp70 expression but failed to reduce LPS-induced apoptosis; VEGF addition did not protect cells against LPS-induced apoptosis at any dose tested. Nevertheless, when treatments were associated, a reduction of LPS-induced apoptosis was always observed; the reduction was maximal when all the treatments (HS + Hemin + VEGF) were associated. In conclusion, this study demonstrates that LPS is effective in evoking "the heat shock response" with an increase of nonspecific protective molecules (namely Hsp70 and Hsp32) and of VEGF, a specific EC growth factor. The protective role of Hsp32 was also demonstrated. Further investigations are required to clarify the synergic effect of Hsp32, Hsp70, and VEGF, thus elucidating the possible interaction between these molecules.

Animals↗

PubMed2004

Expression of cytoprotective proteins, heat shock protein 70 and metallothioneins, in tissues of Ostrea edulis exposed to heat and heavy metals.

Heat shock proteins (Hsps) are constitutively expressed in cells and involved in protein folding, assembly, degradation, intracellular localization, etc, acting as molecular chaperones. However, their overexpression represents a ubiquitous molecular mechanism to cope with stress. Hsps are classified into families, and among them the Hsp70 family appears to be the most evolutionary preserved and distributed in animals. In this study, the expression of Hsp70 and the related messenger ribonucleic acid (mRNA) has been studied in Ostrea edulis after exposure to heat and heavy metals; moreover, levels of metallothioneins (MTs), another class of stress-induced proteins, have contemporaneously been assessed in the same animals. Thermal stress caused the expression of a 69-kDa inducible isoform in gills of O edulis but not in the digestive gland. Northern dot blot analysis confirmed that the transcription of Hsp69-mRNA occurs within 3 hours of stress recovery after oyster exposure at 32 and 35 degrees C. Hsp69-mRNA transcripts were not present in the gills of animals exposed to 38 degrees C after 3 hours of poststress recovery, but they were detected after 24 hours. The expression of the 69-kDa protein in O edulis exposed to 38 degrees C was rather low or totally absent, suggesting that the biochemical machinery at the base of the heat shock response is compromised. Together with the expected increase in MT content, the oysters exposed to Cd showed a significant enhancement of Hsp70, although there was no clear appearance of Hsp69. Interestingly, the levels of MT were significantly increased in the tissues of individuals exposed to thermal stress. Unlike oysters, heat did not provoke the expression of inducible Hsp isoforms in Mytilus galloprovincialis, Tapes philippinarum, and Scapharca inaequivalvis, although it significantly enhanced the expression of constitutive proteins of the 70-kDa family. The expression of newly synthesized Hsp70 isoforms does not seem therefore a common feature in bivalves exposed to thermal stress.

Animals↗

PubMed1990

Lysis of interferon-gamma activated Schwann cell by cross-reactive CD8+ alpha/beta T cells with specificity for the mycobacterial 65 kd heat shock protein.

Heat shock protein (hsp) 65 is a major T cell antigen of Mycobacterium leprae. The hsp 65 of M. leprae is nearly identical in M. bovis/M. tuberculosis (greater than 95% protein sequence homology) and surprisingly similar in man (65% protein sequence homology). Recently, we had provided evidence in a murine model that CD8+ T cells recognize and lyse Schwann cells presenting M. leprae antigen in the context of major histocompatibility (MHC) class I gene products. Because murine Schwann cells are class I negative, antigen presentation requires prior stimulation with interferon-gamma (IFN-gamma). CD8+ T cells were activated against tryptic fragments of mycobacterial hsp 65. These T cells recognized epitopes of hsp 65 which had been generated through the cytoplasmic class I processing pathway. They were also capable of lysing Schwann cells which had been activated by IFN-gamma and not primed with nominal hsp 65 peptides. In contrast, T cells activated against tryptic ova peptides only lysed Schwann cells which had been both stimulated with IFN-gamma and primed with ova peptides. Evidence is presented that class I (H-2D) restricted, CD8+ alpha/beta T lymphocytes with specificity for the mycobacterial hsp 65 recognize IFN-gamma-stimulated Schwann cells probably because they are specific for a(n) epitope(s) shared by the bacterial hsp and a host cognate. Activation of autoreactive T cells with specificity to shared epitopes could contribute to nerve damage in tuberculoid leprosy which is characterized by low to absent M. leprae in Schwann cells.

Animals↗

PubMed1997

Aldosterone and dexamethasone stimulate calcineurin activity through a transcription-independent mechanism involving steroid receptor-associated heat shock proteins.

Heat shock proteins (HSP) are components of the steroid receptor complex and are released into the cell cytosol after hormone binding. We tested whether HSPs released from steroid receptors mediate an increase in calcineurin phosphatase activity by steroid hormones. Aldosterone increased calcineurin activity in microdissected rat cortical collecting ducts (CCD) and connecting tubules, but not in proximal tubules, medullary thick ascending limb, or outer medullary collecting ducts. In contrast, 5 microM dexamethasone increased calcineurin activity in both CCD and proximal tubules. Aldosterone increased CCD calcineurin activity after 30 min and this response was blocked by spironolactone, but not by actinomycin D. An antibody recognizing HSP-56 did not change basal calcineurin activity, but completely blocked the stimulation of calcineurin by aldosterone. Rapamycin, an immunosuppressive drug that stabilizes the HSP-steroid receptor complex, also blocked the aldosterone response, whereas HSP-90 or HSP-70 increased calcineurin activity in permeabilized CCD. In summary, (a) aldosterone increases calcineurin activity in CCD through a transcription-independent process; (b) maneuvers inactivating HSP-56 or slowing HSP disassociation from the receptor complex blocks stimulation of calcineurin by steroid hormones; (c) HSP-90 and HSP-70 increase CCD calcineurin activity in the absence of steroid hormone. We conclude that HSPs released from transformed steroid receptors can stimulate calcineurin activity through a transcription-independent pathway.

Adrenalectomy↗

PubMed2006

A novel HSF1-mediated death pathway that is suppressed by heat shock proteins.

Heat shock response is an adoptive response to proteotoxic stress, and a major heat shock transcription factor 1 (HSF1) has been believed to protect cells from cell death by inducing heat shock proteins (Hsps) that assist protein folding and prevent protein denaturation. However, it is revealed recently that HSF1 also promotes cell death of male germ cells. Here, we found a proapoptotic Tdag51 (T-cell death associated gene 51) gene as a direct target gene of HSF1. Heat shock and other stresses induced different levels of Hsps and Tdag51, which depend on cell types. Hsps bound directly to the N-terminal pleckstrin-homology like (PHL) domain of Tdag51, and suppressed death activity of the C-terminal proline/glutamine/histidine-rich domain. Tdag51, but not major Hsps, were induced in male germ cells exposed to high temperatures. Analysis of Tdag51-null testes showed that Tdag51 played substantial roles in promoting heat shock-induced cell death in vivo. These data suggest that cell fate on proteotoxic condition is determined at least by balance between Hsp and Tdag51 levels, which are differently regulated by HSF1.

Animals↗

PubMed2000

Production and characterization of a monoclonal antibody specific to the human 70-kDa heat shock protein.

Heat shock protein 70 (hsp 70) plays major roles in apoptosis prevention and thermotolerance as well as molecular chaperoning. It is also expressed on the surface of human tumor cells, but not on normal cells, suggesting that hsp70 may be some tumor-associated antigen. To investigate the diverse functions of the protein species, various types of transgenic mice or cell models overexpressing human hsp70 have been made. In these models a monoclonal antibody (MAb) specific for the human hsp70 is highly desirable to distinguish the human from the endogenous mouse hsp70. It proved difficult to make this species-specific MAb, because the hsp70 homologues are members of a family of highly conserved, abundant, and ubiquitous proteins expressed in organisms ranging from bacteria to humans. In the present study, we prepared four MAbs against human hsp70. Three, HD 5, HD 7 and HD 11, recognize human and mouse hsp70. One, though, HD 8, recognizes human hsp70, but not mouse hsp70. By Western blot analysis of hsp70 deletion mutants, the epitope of the HD 8 MAb was determined as the 585-616 amino acid region of the human hsp70, a region with relatively low homology to mouse hsp70.

Animals↗

PubMed2005

Scant activation of CD8 T cells by antigen loaded on heat shock protein.

Heat shock proteins (HSP) not only function as chaperones for denatured proteins but also for antigenic peptides, thus inducing protective T cell responses. Here we show that vaccination with peptide-loaded HSP70 causes initial interferon-gamma production by murine CD8 T cells but no T cell expansion. These CD8 T cells lacked cytotoxic activity in vitro and in vivo, which was not due to apoptosis. Restimulation with peptide-pulsed dendritic cells both bypassed the proliferative block and suspended the non-protective state of CD8 T lymphocytes in an infection model with the bacterial pathogen, Listeria monocytogenes. Cotransfer of antigen-specific CD4 T cells circumvented the proliferative arrest of CD8 T cells. Our data suggest that HSP vaccines induce CD8 T cell unresponsiveness unless proficient help is provided. Assuming that this model reflects the antigenically experienced human condition where immunological space is restricted and any T cell response possibly leads to suppression of heterologous reactions, our findings bear implications for rational vaccination protocols including those for immunocompromised patients.

Antigens↗