Gene/Protein Disease Symptom Drug Enzyme Compound
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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article we show a Triton-insoluble, intermediate filament-associated protein of approximately 70 kD to be expressed ubiquitously in diverse mammalian cell types. This protein, assigned the name beta-internexin, exhibits extreme homology in each of the various cell lines as demonstrated by identical limited peptide maps, similar mobilities on two-dimensional gels, and detection in Triton-soluble and -insoluble extracts. beta-Internexin also shares some degree of homology with alpha-internexin, an intermediate filament-associated protein isolated and purified from rat spinal cord, which accounts for the immunologic cross-reactivity displayed by these polypeptides. Light microscopic immunolocalization of beta-internexin with a monoclonal antibody (mAb-IN30) reveals it to be closely associated with the vimentin network in fibroblasts. The antigen is also observed to collapse with the vimentin reticulum during the formation of a juxtanuclear cap induced by colchicine treatment. Ultrastructural localization, using colloidal gold, substantiates the affinity of beta-internexin for cytoplasmic filaments and, in addition, demonstrates its apparent exclusion from the intranuclear filament network. We examine also the resemblance of beta-internexin to a microtubule-associated polypeptide and the constitutively synthesized mammalian heat shock protein (HSP 68/70).
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PMID:beta-Internexin, a ubiquitous intermediate filament-associated protein. 390 89

We have described two mitochondrial (mt) myopathy patients with reduced activities of various mt enzymes associated with significantly decreased amounts of heat shock protein 60 (hsp60). Experimental evidence suggested that the lack of hsp60 was the primary defect. Since hsp60 is essential for the proper folding of enzyme subunits in the mt matrix a partial deficiency of this protein can explain the observed defects of the mitochondria. Here we report on morphological studies aimed at obtaining more insight into the relation between lack of hsp60 and pathological changes of the mitochondria. Under standard culture conditions mitochondria in the partially hsp60 deficient fibroblasts showed profound morphological aberrations. In contrast, the mitochondria in fibroblasts from a MELAS patient and a cytochrome c oxidase-deficient patient appeared normal. Under stress conditions the integrity of the hsp60 deficient mitochondria declined even further: heat shock induced a temporary collapse of the electrochemical potential across the inner mt membrane, but did not affect the ultrastructure of the mitochondria; prolonged growth in confluent cultures resulted in decrease in mt number. The altered mt morphology in the hsp60 deficient cells is probably indicative of the severely impaired mt metabolism whereas the decreased stress tolerance is likely to be a direct result of paucity of the heat shock protein. Both variables are potentially useful in the diagnosis and molecular characterization of mt disorders with systemic manifestation and multiple enzyme deficiency.
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PMID:Morphology of the mitochondria in heat shock protein 60 deficient fibroblasts from mitochondrial myopathy patients. Effects of stress conditions. 758 46

HSP27 and alphaB-crystallin are both members of the small heat shock protein family. alphaB-crystalllin has been proposed to modulate intermediate filaments and recently a mutation in alphaB-crystallin has been identified as the genetic basis of desmin related myopathy. This disease is characterised in its pathology by aggregates of intermediate filaments associated with alphaB-crystallin. Here we report that HSP27 like alphaB-crystallin is associated with glial fibrillary acidic protein and vimentin intermediate filament networks in unstressed U373MG astrocytoma cells. HSP27 is also associated with keratin filaments in MCF7 cells, indicating that this association is not restricted to a particular intermediate filament type. The association of sHSPs with both the soluble and filamentous intermediate filament fractions of U373 cells was demonstrated biochemically. Heat shock or drug treatments induced a co-collapse of intermediate filaments and associated small heat shock proteins. These data show that the presence of HSP27 or alphaB-crystallin could not prevent filament collapse and suggest that the purpose of this association is more than just filament binding. Indeed, in U373MG cells the intermediate filament association with small heat shock proteins is similar to that observed for another protein chaperone, HSC70. In order to discern the effect of different chaperone classes on intermediate filament network formation and maintenance, several in vitro assays were assessed. Of these, falling ball viscometry revealed a specific activity of small heat shock proteins compared to HSC70 that was apparently inactive in this assay. Intermediate filaments form a gel in the absence of small heat shock proteins. In contrast, inclusion of alphaB-crystallin or HSP27 prevented gel formation but not filament assembly. The transient transfection of GFAP into MCF7 cells was used to show that the induction of a completely separate network of intermediate filaments resulted in the specific association of the endogenous HSP27 with these new GFAP filaments. These data lead us to propose that one of the major functions of the association of small heat shock proteins with intermediate filaments is to help manage the interactions that occur between filaments in their cellular networks. This is achieved by protecting filaments against those non-covalent interactions that result when they come into very close proximity as seen from the viscosity experiments and which have the potential to induce intermediate filament aggregation as seen in some disease pathologies.
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PMID:Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. 1036 40

Chemical warfare threats require the development of diverse models for the assessment of countermeasures. Human skin products, Skin2 (differentiating keratinocytes on a fibroblast-collagen matrix) and EpiDerm (differentiating keratinocytes) were exposed (2 h) to the sulfur mustard 2-chloroethyl ethyl sulfide (CEES, 1-2 mg l(-1) min(-1)) in humidified air or to humidified air alone. Tissues were evaluated histologically, ultrastructurally and for viability 22 h later; media and tissues were also analyzed for inflammatory mediators. Histology showed that CEES induced the separation of dermal and epidermal regions in Skin2 with severe damage to basal keratinocytes. Histology and electron microscopy of both products revealed condensation of nuclear chromatin, retraction of spinous processes, collapse of the tonofibrillar network and cytoplasmic vacuolization and blebbing in those cells with loss of pseudobasement membrane integrity. Exposure of Skin2 to CEES increased extracellular interleukin-1alpha (IL-1alpha), prostaglandin-E2 (PGE2) and especially IL-1 receptor antagonist (IL-1Ra) release (56,334 vs 84,614 pg ml(-1)), but decreased interleukin-6 (IL-6, 4,755 vs 351 pg ml(-1)). Exposure of EpiDerm to CEES led to unaffected extracellular and reduced intracelluar IL-1alpha (371 vs 92 pg ml(-1)). Extracellular IL-1Ra greatly increased (2,375 vs 24,875 pg ml(-1)), whereas cellular levels decreased (16,5425 vs 96,625 pg ml(-1)). Extracellular (224 vs 68 pg ml(-1)) and intracellular (485 vs 233 pg ml(-1)) soluble interleukin-1 receptor H (sIL-1RII) decreased. Prostanglandin E2 increased (1,835 vs 2,582 pg ml(-1)), whereas heat shock protein 70A (Hsp70A) remained statistically unchanged (57,000 vs 96,000 pg ml(-1)). Failure to obtain a heat shock response to CEES may contribute to the susceptibility of tissue to the alkylating agent. Consistent and marked responses of cellular and extracellular IL-1Ra to CEES suggest a potential for use as a tissue status marker and primary antiinflammatory regulator in skin.
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PMID:Effects of CEES on inflammatory mediators, heat shock protein 70A, histology and ultrastructure in two skin models. 1142 19

Heat shock transcription factors (Hsfs) are major transactivators of heat shock protein (Hsp) genes in the response to stress stimuli, but are also thought to be involved in embryonic development and spermatogenesis. Among the three known mammalian Hsfs, Hsf1 is recognized as the most effective transactivator of Hsps in response to thermal challenge, but the role of Hsf2 in regulation of genes under normal or increased stress conditions in vivo remains elusive. To study its physiological function in vivo, we generated mice deficient in hsf2 by gene targeting. We report here that hsf2(-/-) mice exhibit multiple phenotypes, including an increased prenatal lethality occurring between mid-gestation to birth, with fetal death probably due to central nervous system defects including collapse of the lateral ventricles and ventricular hemorrhages. Approximately 30% of hsf2(-/-) animals surviving to adulthood exhibited brain abnormalities characterized by marked dilation of the third and lateral ventricles. In addition, disruption of hsf2 resulted in reduced female fertility; however, despite ubiquitous expression in the testes and markedly reduced testis size and sperm count, only a small reduction in fertility was apparent in hsf2(-/-) male mice. Immunoblotting and gene expression microarray analysis of hsf2(-/-) embryos did not reveal reduced Hsp expression levels, indicating that the defects observed in hsf2(-/-) embryos may not result from disruption of Hsp expression. These findings suggest that hsf2 has a major function in controlling expression of genes important for embryonic development and maintenance of sperm production.
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PMID:Targeted disruption of the heat shock transcription factor (hsf)-2 gene results in increased embryonic lethality, neuronal defects, and reduced spermatogenesis. 1274 67

Schizophrenia is a serious neuropsychiatric illness estimated to affect approximately 1% of the general population. As part of a genome scan for schizophrenia susceptibility loci, we have previously reported a maximum heterogeneity four-point lod score of 6.50 on chromosome 1q21-22 in a group of 22 medium-sized Canadian families, selected for study because multiple relatives were clinically diagnosed with schizophrenia or schizoaffective disorder. We have now conducted fine mapping of this locus in the same set of individuals using 15 genetic markers spanning an approximately 15-cM interval. Parametric linkage analysis with GENEHUNTER v2.1 and VITESSE v2.0 produced a maximum multipoint heterogeneity lod score of 6.50, with a Zmax-1 support interval of <3 cM, corresponding to approximately 1 Mb. Physical mapping and sequence analysis from this region confirmed the presence of an approximately 81-kb tandem duplication, containing low-affinity IgG receptor genes and heat shock protein genes. The sequences of the two copies of this duplication are approximately 97% identical, which has led to the collapse of the two copies into one in the June 2002 NCBI Build 30 of the Human Genome. This duplication may be involved in genomic instability, leading to gene deletion, and so presents an intriguing candidate locus for schizophrenia susceptibility.
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PMID:Fine mapping of the schizophrenia susceptibility locus on chromosome 1q22. 1277 52

The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a number of other chaperones, promotes the conformational maturation of a large variety of protein kinases. Inhibition of Hsp90 function results in the collapse of the metastable conformation of most of these kinases and leads to their proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90 inhibitors have been developed in recent years. Some of these inhibitors are also involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti-cancer drugs. Here we review these novel protein kinase inhibitors and their emerging role in various cellular processes, apart from their inhibition of Hsp90 protein function. We focus not only on Hsp90-tumor progression, but also on cytoarchitecture, as the higher levels of cellular organization need constant remodeling, where the role of Hsp90 requires investigation. Our last major aspect deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant effects.
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PMID:Inhibition of Hsp90: a new strategy for inhibiting protein kinases. 1502 64

The biochemical function of many parts of the genome, transcriptome, proteome, and interactome remain largely unknown. We propose that portions of these fundamental building blocks of life have no current biochemical function per se. Rather, sections of these "omes" may contribute to an inventory of biochemical parts and circuits that participate in the development of emergent functions. Low fidelity deoxyribonucleic acid replication, transcription, translation, and post-translational modification all represent potential mechanisms to produce an inventory of parts. Stochastic processes that influence the conformations of ribonucleic acid molecules and proteins may also contribute to potential biochemical inventory. Some components of the biochemical inventory may enable future adaptations, some may produce disease, and some may remain useless. The function of many of these components await discovery, not by science, but by evolution. While carrying such purposeless biochemical units may appear to dilute fitness by exacting a thermodynamic cost, we argue that net fitness becomes enhanced when considering the value for potential future innovations. One can envision components that intermingle, interact, and act out mock pathways, but in most cases remain molecular bridesmaids. Given sufficiently low thermodynamic cost, such stochastic cycling may persist until a markedly advantageous or cataclysmically disadvantageous trait emerges. Maladaptive screening and utilization of inventory content can lead to disease phenotypes, a process buffered and regulated in part by the heat shock protein and stress response network. Whereas failure of the ubiquitin pathway to recycle misfolded proteins has become increasingly recognized as a source of disease, protein misfolding may itself represent one step in a process that maximizes functional innovation through increasing proteomic diversity. Fractal correlates of these processes occur at the organizational level of cells and organisms. That the abnormal accumulation of units induces local collapse may serve to limit the extension of damage to the greater system at large. The immune and cognitive systems that selectively sample and prune environmental content may serve as additional portals for innovation.
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PMID:Efficient inefficiency: biochemical "junk" may represent molecular bridesmaids awaiting emergent function as a buffer against environmental fluctuation. 1658 Nov 98

AlphaB-crystallin homology, heat stress induction and chaperone activity suggested that a previously encloned gene product is a novel small heat shock protein (Hsp16.2). Suppression of Hsp16.2 by siRNA sensitized cells to hydrogen peroxide or taxol induced cell-death. Over-expressing of Hsp16.2 protected cells against stress stimuli by inhibiting cytochrome c release from the mitochondria, nuclear translocation of AIF and endonuclease G, and caspase 3 activation. Recombinant Hsp16.2 protected mitochondrial membrane potential against calcium induced collapse in vitro indicating that Hsp16.2 stabilizes mitochondrial membrane systems. Hsp16.2 formed self-aggregates and bound to Hsp90. Inhibition of Hsp90 by geldanamycin diminished the cytoprotective effect of Hsp16.2 indicating that this effect was Hsp90-mediated. Hsp16.2 over-expression increased lipid rafts formation as demonstrated by increased cell surface labeling with fluorescent cholera toxin B, and increased Akt phosphorylation. The inhibition of PI-3-kinase-Akt pathway by LY-294002 or wortmannin significantly decreased the protective effect of the Hsp16.2. These data indicate that the over-expression of Hsp16.2 inhibits cell death via the stabilization of mitochondrial membrane system, activation of Hsp90, stabilization of lipid rafts and by the activation of PI-3-kinase-Akt cytoprotective pathway.
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PMID:Inhibition of cell death by a novel 16.2 kD heat shock protein predominantly via Hsp90 mediated lipid rafts stabilization and Akt activation pathway. 1713 96

In eukaryotes, the ubiquitin-proteasome system (UPS) is responsible for the degradation of most proteins. Proteasome inhibition, which has been associated with various diseases, can cause alterations in various intracellular processes including the expression of heat shock protein (hsp) genes. In this study, we show that celastrol, a quinone methide triterpene and anti-inflammatory agent, inhibited proteasome activity and enhanced HSP accumulation in Xenopus laevis A6 kidney epithelial cells. Treatment of cells with celastrol induced the accumulation of ubiquitinated protein and inhibited chymotrypsin-like activity. This was accompanied by a dose- and time-dependent accumulation of HSP30 and HSP70. Celastrol-induced HSP accumulation was mediated by HSF1-DNA binding activity since this response was inhibited by the HSF1 activation inhibitor, KNK437. Simultaneous exposure of cells with celastrol plus either mild heat shock or the proteasome inhibitor, MG132, produced an enhanced accumulation of HSP30 that was greater than the sum of the individual stressors alone. Immunocytochemical analysis revealed that celastrol-induced HSP30 accumulation occurred in the cytoplasm in a granular pattern supplemented with larger circular HSP30 staining structures. HSP30 was also noted in the nucleus with less staining in the nucleolus. In some cells, celastrol induced the collapse of the actin cytoskeleton and conversion to a rounder morphology. In conclusion, this study has shown that celastrol inhibited proteasome activity and induced HSF1-mediated expression of hsp genes in amphibian cells.
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PMID:Celastrol can inhibit proteasome activity and upregulate the expression of heat shock protein genes, hsp30 and hsp70, in Xenopus laevis A6 cells. 2018 6


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