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Steven S. Witkin - One of the best experts on this subject based on the ideXlab platform.
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induction of the 70 kda Heat Shock Protein stress response inhibits autophagy possible consequences for pregnancy outcome
Journal of Maternal-fetal & Neonatal Medicine, 2016Co-Authors: Tomi T Kanninen, Giovanni Sisti, Steven S. WitkinAbstract:AbstractAim: The induction of Heat Shock Protein synthesis and activation of autophagy are intracellular processes stimulated under adverse conditions. We evaluated the relationship between intracellular concentrations of the inducible 70 kDa Heat Shock Protein (hsp70) and autophagy induction in human peripheral blood mononuclear cells (PBMCs) following exposure to sera from pregnant and non-pregnant women.Methods: Autophagy was induced in PBMCs by incubation for 48 h with sera from 42 pregnant women at mid-gestation and 45 non-pregnant women. Intracellular concentrations of hsp70 and p62 were measured by ELISA. p62 is a cytoplasmic Protein that is consumed during autophagy induction. Its concentration in the cytoplasm is inversely proportional to the extent of autophagy induction (high p62 = low autophagy).Results: The p62 concentration was highly correlated with the hsp70 level utilizing sera from both pregnant (Spearman r = 0.4731, p = 0.0015) and non-pregnant (Spearman r = 0.6214, p < 0.0001) women. M...
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association between vaginal 70 kd Heat Shock Protein interleukin 1 receptor antagonist and microbial flora in mid trimester pregnant women
American Journal of Obstetrics and Gynecology, 2004Co-Authors: Mehmet R Genc, Andrew B Onderdonk, Mary L Delaney, Ann Marie Bongiovanni, Emre Karasahin, Steven S. WitkinAbstract:Objective This study investigated the association among the inducible 70-kd Heat Shock Protein, cytokines, and microbial flora in the vagina in mid trimester pregnant women and subsequent preterm delivery. Study design Vaginal samples from 205 pregnant women, which were collected at 18 to 22 weeks of gestation, were analyzed for qualitative and quantitative vaginal microflora and for 70-kd Heat Shock Protein, interleukin-1β, interleukin-1 receptor antagonist, and tumor necrosis factor-α by enzyme-linked immunosorbent assay. Pregnancy outcome data were obtained subsequently. Results The 70-kd Heat Shock Protein was detected in 38 vaginal samples (18.5%). Its presence was associated with elevated vaginal pH, a diagnosis of bacterial vaginosis, and elevated interleukin-1 receptor antagonist levels (P 80% increase in median vaginal concentration of interleukin-1 receptor antagonist (P Conclusion Vaginal 70-kd Heat Shock Protein expression is associated with the down-regulation of the proinflammatory immune response to abnormal vaginal flora in mid trimester pregnant women.
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polymorphisms in the tumor necrosis factor α gene at position 308 and the inducible 70 kd Heat Shock Protein gene at position 1267 in multifetal pregnancies and preterm premature rupture of fetal membranes
American Journal of Obstetrics and Gynecology, 2004Co-Authors: Robin B Kalish, Santosh Vardhana, Meruka Gupta, Sriram C Perni, Stephen T Chasen, Steven S. WitkinAbstract:Objective The purpose of this study was to determine the relationship between preterm premature rupture of membranes, tumor necrosis factor-α, and Heat Shock Protein-70 gene polymorphisms in multifetal gestations. Study design Buccal swabs from 101 mother-neonate pairs of multifetal pregnancies were tested for single nucleotide polymorphisms at position −308 of the tumor necrosis factor-α gene and +1267 of the Heat Shock Protein–70 gene. Pregnancy outcome data were obtained subsequently. Results Tumor necrosis factor-α allele 2 carriage by the first-born occurred in 10 of 27 pregnancies (37.0%) that resulted in preterm premature rupture of membranes compared with 6 of 67 pregnancies (9.0%) without preterm premature rupture of membranes ( P =.002). The allele frequency of tumor necrosis factor-α allele 2 and Heat Shock Protein–70 allele 2 in the first born was higher in pregnancies that were complicated by preterm premature rupture of membranes (18.5% vs 4.5%; P =.003; and 57.7% vs 41.3%; P =.04, respectively). There was no relationship between tumor necrosis factor-α allele 2 or Heat Shock Protein-70 allele 2 carriage by the second fetus or mother and preterm premature rupture of membranes. Conclusion Tumor necrosis factor-α allele 2 and/or Heat Shock Protein-70 allele 2 carriage by the first-born fetus is associated with preterm premature rupture of membranes in multifetal pregnancies.
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vaginal Heat Shock Protein expression in symptom free women with a history of recurrent vulvovaginitis
American Journal of Obstetrics and Gynecology, 1999Co-Authors: Paulo Cesar Giraldo, Irina Korneeva, Jose Antonio Simoes, A Neuer, Ayrton Ribeirofilho, Steven S. WitkinAbstract:Abstract Objectives: The cause of recurrent vulvovaginitis remains unexplained in most cases. Heat Shock Protein synthesis is induced under conditions of stress; its presence in vaginal samples from women who were between episodes of recurrent vulvovaginitis thus might reflect a persistent perturbation in the local milieu. Study Design: We undertook an evaluation by means of enzyme-linked immunosorbent assay of 60-kd Heat Shock Protein and inducible 70-kd Heat Shock Protein expressions in vaginal wash samples from 24 symptom-free women with a history of recurrent vulvovaginitis and 19 matched control subjects. The samples were also tested for Candida albicans , Chlamydia trachomatis , Ureaplasma urealyticum , Mycoplasma hominis, and human papillomavirus by polymerase chain reaction; for bacterial vaginosis by clinical and microbiologic evaluation; and for interleukin 10, interleukin 1, interleukin 8, RANTES, and eotaxin by enzyme-linked immunosorbent assay. Results: The presence of 60-kd Heat Shock Protein was detected in 11 women with recurrent vulvovaginitis (45.8%) and 1 control subject (5.3%, P = .005). Similarly, 70-kd Heat Shock Protein was present in 8 patients with recurrent vulvovaginitis (33.3%) and no control subjects ( P = .005). The presence of 60-kd Heat Shock Protein and the presence of 70-kd Heat Shock Protein were correlated with each other ( P = .02), as were both 60-kd Heat Shock Protein ( P = .006) and 70-kd Heat Shock Protein ( P = .01) correlated with IL-10. There was no relation between the presence of 60-kd Heat Shock Protein or 70-kd Heat Shock Protein and detection of IL-1, IL-8, or any microorganism. Conclusion: The expression of Heat Shock Proteins and IL-10 in the vaginas of women with a history of recurrent vulvovaginitis but not in the vaginas of control subjects suggests the existence of differences in the vaginal milieu between the 2 groups, even when both are without vaginal symptoms. (Am J Obstet Gynecol 1999;180:524-9.)
Jack A M Leunissen - One of the best experts on this subject based on the ideXlab platform.
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genealogy of the α crystallin small Heat Shock Protein superfamily
International Journal of Biological Macromolecules, 1998Co-Authors: W.w. De Jong, Gertjan Caspers, Jack A M LeunissenAbstract:Sequences of 40 very diverse representatives of the α-crystallin–small Heat-Shock Protein (α-Hsp) superfamily are compared. Their characteristic C-terminal `α-crystallin domain' of 80–100 residues contains short consensus sequences that are highly conserved from prokaryotes to eukaryotes. There are, in addition, some positions that clearly distinguish animal from non-animal α-Hsps. The α-crystallin domain is predicted to consist of two hydrophobic β-sheet motifs, separated by a hydrophilic region which is variable in length. Combination of a conserved α-crystallin domain with a variable N-terminal domain and C-terminal extension probably modulates the properties of the various α-Hsps as stress-protective and structural oligomeric Proteins. Phylogeny reconstruction indicates that multiple α-Hsps were already present in the last common ancestor of pro- and eukaryotes. It is suggested that during eukaryote evolution, animal and non-animal α-Hsps originated from different ancestral gene copies. Repeated gene duplications gave rise to the multiple α-Hsps present in most organisms.
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genealogy of the α crystallin small Heat Shock Protein superfamily
International Journal of Biological Macromolecules, 1998Co-Authors: W.w. De Jong, Gertjan Caspers, Jack A M LeunissenAbstract:Sequences of 40 very diverse representatives of the alpha-crystallin-small Heat-Shock Protein (alpha-Hsp) superfamily are compared. Their characteristic C-terminal 'alpha-crystallin domain' of 80-100 residues contains short consensus sequences that are highly conserved from prokaryotes to eukaryotes. There are, in addition, some positions that clearly distinguish animal from non-animal alpha-Hsps. The alpha-crystallin domain is predicted to consist of two hydrophobic beta-sheet motifs, separated by a hydrophilic region which is variable in length. Combination of a conserved alpha-crystallin domain with a variable N-terminal domain and C-terminal extension probably modulates the properties of the various alpha-Hsps as stress-protective and structural oligomeric Proteins. Phylogeny reconstruction indicates that multiple alpha-Hsps were already present in the last common ancestor of pro- and eukaryotes. It is suggested that during eukaryote evolution, animal and non-animal alpha-Hsps originated from different ancestral gene copies. Repeated gene duplications gave rise to the multiple alpha-Hsps present in most organisms.
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evolution of the alpha crystallin small Heat Shock Protein family
Molecular Biology and Evolution, 1993Co-Authors: W.w. De Jong, Jack A M Leunissen, Christina E M VoorterAbstract:Abstract The common characteristic of the alpha-crystallin/small Heat-Shock Protein family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens Proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa Heat-Shock Proteins, this family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small Heat-Shock Proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic Proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small Heat-Shock Protein. The homologous sequences constitute the C-terminal halves of the Proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this Protein family. Analysis of the phylogenetic tree and comparison of the biological properties of the various Proteins in this family suggest the following scenario for its evolution: The primordial role of the small Heat-Shock Protein family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens Protein in vertebrates. It has recently been demonstrated that, like the other Heat-Shock Proteins, the alpha-crystallins and small Heat-Shock Proteins function as molecular chaperones, preventing undesired Protein-Protein interactions and assisting in refolding of denatured Proteins. Many of the small Heat-Shock Proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small Heat-Shock Proteins, they may also be involved in signal transduction. The reversible phosphorylation of these Proteins appears to be important in this respect.
W.w. De Jong - One of the best experts on this subject based on the ideXlab platform.
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genealogy of the α crystallin small Heat Shock Protein superfamily
International Journal of Biological Macromolecules, 1998Co-Authors: W.w. De Jong, Gertjan Caspers, Jack A M LeunissenAbstract:Sequences of 40 very diverse representatives of the α-crystallin–small Heat-Shock Protein (α-Hsp) superfamily are compared. Their characteristic C-terminal `α-crystallin domain' of 80–100 residues contains short consensus sequences that are highly conserved from prokaryotes to eukaryotes. There are, in addition, some positions that clearly distinguish animal from non-animal α-Hsps. The α-crystallin domain is predicted to consist of two hydrophobic β-sheet motifs, separated by a hydrophilic region which is variable in length. Combination of a conserved α-crystallin domain with a variable N-terminal domain and C-terminal extension probably modulates the properties of the various α-Hsps as stress-protective and structural oligomeric Proteins. Phylogeny reconstruction indicates that multiple α-Hsps were already present in the last common ancestor of pro- and eukaryotes. It is suggested that during eukaryote evolution, animal and non-animal α-Hsps originated from different ancestral gene copies. Repeated gene duplications gave rise to the multiple α-Hsps present in most organisms.
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genealogy of the α crystallin small Heat Shock Protein superfamily
International Journal of Biological Macromolecules, 1998Co-Authors: W.w. De Jong, Gertjan Caspers, Jack A M LeunissenAbstract:Sequences of 40 very diverse representatives of the alpha-crystallin-small Heat-Shock Protein (alpha-Hsp) superfamily are compared. Their characteristic C-terminal 'alpha-crystallin domain' of 80-100 residues contains short consensus sequences that are highly conserved from prokaryotes to eukaryotes. There are, in addition, some positions that clearly distinguish animal from non-animal alpha-Hsps. The alpha-crystallin domain is predicted to consist of two hydrophobic beta-sheet motifs, separated by a hydrophilic region which is variable in length. Combination of a conserved alpha-crystallin domain with a variable N-terminal domain and C-terminal extension probably modulates the properties of the various alpha-Hsps as stress-protective and structural oligomeric Proteins. Phylogeny reconstruction indicates that multiple alpha-Hsps were already present in the last common ancestor of pro- and eukaryotes. It is suggested that during eukaryote evolution, animal and non-animal alpha-Hsps originated from different ancestral gene copies. Repeated gene duplications gave rise to the multiple alpha-Hsps present in most organisms.
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evolution of the alpha crystallin small Heat Shock Protein family
Molecular Biology and Evolution, 1993Co-Authors: W.w. De Jong, Jack A M Leunissen, Christina E M VoorterAbstract:Abstract The common characteristic of the alpha-crystallin/small Heat-Shock Protein family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens Proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa Heat-Shock Proteins, this family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small Heat-Shock Proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic Proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small Heat-Shock Protein. The homologous sequences constitute the C-terminal halves of the Proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this Protein family. Analysis of the phylogenetic tree and comparison of the biological properties of the various Proteins in this family suggest the following scenario for its evolution: The primordial role of the small Heat-Shock Protein family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens Protein in vertebrates. It has recently been demonstrated that, like the other Heat-Shock Proteins, the alpha-crystallins and small Heat-Shock Proteins function as molecular chaperones, preventing undesired Protein-Protein interactions and assisting in refolding of denatured Proteins. Many of the small Heat-Shock Proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small Heat-Shock Proteins, they may also be involved in signal transduction. The reversible phosphorylation of these Proteins appears to be important in this respect.
Len Neckers - One of the best experts on this subject based on the ideXlab platform.
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Heat Shock Protein 90: The Cancer Chaperone
Journal of Biosciences, 2007Co-Authors: Len NeckersAbstract:Heat Shock Protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signalling Proteins, as well as multiple mutated, chimeric, and/or over-expressed signalling Proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple cellular signalling pathways. By inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90 inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client Proteins are neurotoxic, these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90 inhibitors in treating multiple pathologies involving neurodegeneration.
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Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells
Clinical Cancer Research, 2007Co-Authors: Wanping Xu, Len NeckersAbstract:Heat Shock Protein 90 (Hsp90) is a molecular chaperone required for the stability and function of several conditionally activated and/or expressed signaling Proteins as well as multiple mutated, chimeric, and/or overexpressed signaling Proteins, which promote cancer cell growth and/or survival (see
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Heat Shock Protein 90.
Current Opinion in Oncology, 2003Co-Authors: Len NeckersAbstract:PURPOSE OF REVIEW: Heat Shock Protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling Proteins, as well as multiple mutated, chimeric, or overexpressed signaling Proteins, which promote cancer cell growth or survival or both. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client Proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial, and several Phase II trials are in progress. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. RECENT FINDINGS: Recently identified clients of Hsp90 participate, frequently in overlapping pathways, in mediating cancer cell survival. These include Akt, Her2, and HIF-1 alpha. Thus, by inhibiting multiple survival pathways used by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Furthermore, Hsp90 modulates androgen receptor activity and the activity of several mutated kinases characteristic of several leukemias and lymphomas, making Hsp90 inhibition an attractive modality in these cases. SUMMARY: Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should augment the treatment of multiple forms of cancer.
Joram Piatigorsky - One of the best experts on this subject based on the ideXlab platform.
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alpha crystallin small Heat Shock Protein has autokinase activity
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Marc Kantorow, Joram PiatigorskyAbstract:The alpha-crystallins (alpha A and alpha B) are major water-soluble Proteins of the transparent eye lens that are expressed in a variety of tissues and can function as molecular chaperones. alpha B-crystallin is also a small Heat Shock Protein associated with numerous degenerative diseases and abnormal growth patterns. Previous experiments have shown that alpha A-and alpha B-crystallin are phosphorylated on specific serine residues by a cAMP-dependent pathway. Here we provide evidence that either total bovine alpha-crystallin or its isolated polypeptides can autophosphorylate serine by a cAMP-independent mechanism in the presence of Mg2+ and [gamma-32P]ATP; the autophosphorylated products isoelectrically focus with the authentic phosphorylated forms of the alpha-crystallin polypeptides. Thus, the alpha A- and alpha B-crystallin/small Heat Shock Protein polypeptides are enzyme-crystallins which may be involved in metabolic pathways important for the development, maintenance, or pathology of the lens and other tissues.