Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.
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PMID:17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. 1906 30

Plant responses against pathogens cause up- and downward shifts in gene expression. To identify differentially expressed genes in a plant-virus interaction, susceptible tomato plants were inoculated with the potyvirus Pepper yellow mosaic virus (PepYMV) and a subtractive library was constructed from inoculated leaves at 72 h after inoculation. Several genes were identified as upregulated, including genes involved in plant defense responses (e.g., pathogenesis-related protein 5), regulation of the cell cycle (e.g., cytokinin-repressed proteins), signal transduction (e.g., CAX-interacting protein 4, SNF1 kinase), transcriptional regulators (e.g., WRKY and SCARECROW transcription factors), stress response proteins (e.g., Hsp90, DNA-J, 20S proteasome alpha subunit B, translationally controlled tumor protein), ubiquitins (e.g., polyubiquitin, ubiquitin activating enzyme 2), among others. Downregulated genes were also identified, which likewise display identity with genes involved in several metabolic pathways. Differential expression of selected genes was validated by macroarray analysis and quantitative real-time polymerase chain reaction. The possible roles played by some of these genes in the viral infection cycle are discussed.
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PMID:Genome-wide analysis of differentially expressed genes during the early stages of tomato infection by a potyvirus. 1924 29

Our previous study has revealed that heat shock protein (Hsp) 90 can interact with Sp1 to regulate the transcriptional activity of 12(S)-lipoxygenase. Herein, we further found that the interaction between Hsp90 and Sp1 occurred during mitosis. By geldanamycin (GA) treatment and knockdown of Hsp90, we found that this interaction during mitosis was involved in the maintenance of Sp1 stability, and that the phospho-c-Jun N-terminal kinase (JNK)-1 level also decreased. As the JNK-1 was knocked down by the shRNA of JNK-1, Sp1 was degraded through a ubiquitin-dependent proteasome pathway. In addition, for mutation of the JNK-1 phosphorylated residues of Sp1, namely, Sp1(T278/739A) and Sp1(T278/739D), the effect of GA on Sp1 stability was reversed. Finally, based on the involvement of Hsp90 in Sp1 stability, the transcriptional activities of p21(WAF1/CIP1) and 12(S)-lipoxygenase under GA treatment were observed to have decreased. Taken together, Hsp90 is important for maintaining Sp1 stability during mitosis by the JNK-1-mediated phosphorylation of Sp1 to enable division into daughter cells and to regulate the expression of related genes in the interphase.
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PMID:Heat shock protein 90 is important for Sp1 stability during mitosis. 1924 16

In this paper we examined the impact of age on cognitive functions and the age-related modifications of egr1 expression, an inducible transcription factor with a confirmed role in synaptic plasticity and regulation of the proteasome activity, on pet dogs. Additionally, we examined the age-related changes of some elements of the ubiquitin-proteasome system, which is the apparatus that prevents the intracellular accumulation of abnormal proteins. The results of behavioral analysis revealed that old/senior dogs (9-16-year-old) had impaired cognitive performance compared to young/middle-aged dogs (2-8-year-old) in the Reversal Learning task. Taken togheter, the results (age-related decline of Psmd4, Psmb8, CHIP, and egr1 expression; increase of Psmb9 and Hsp90 expression) suggest that the activity of the ubiquitin-proteasome system in the dog hippocampus is a multi-step process, in which abnormal proteins destined for degradation are recognized and destroyed, and shows an age-related decline. The consequent failure of the "protein quality control system" might have detrimental effects on cell physiology and lead to a progressive impairment of cognitive functions.
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PMID:Age-related modifications of egr1 expression and ubiquitin-proteasome components in pet dog hippocampus. 1942 50

Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.
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PMID:Chaperone signalling complexes in Alzheimer's disease. 1944 61

Hypoxia-inducible factor 1 (HIF-1) is a central regulator of the hypoxic response in many cell types. In endothelial cells, HIF-1 induces the expression of key proangiogenic factors to promote angiogenesis. Recent studies have identified Kruppel-like factor 2 (KLF2) as a potent inhibitor of angiogenesis. However, the role of KLF2 in regulating HIF-1 expression and function has not been evaluated. KLF2 expression was induced acutely by hypoxia in endothelial cells. Adenoviral overexpression of KLF2 inhibited hypoxia-induced expression of HIF-1alpha and its target genes such as interleukin 8, angiopoietin-2, and vascular endothelial growth factor in endothelial cells. Conversely, knockdown of KLF2 increased expression of HIF-1alpha and its targets. Furthermore, KLF2 inhibited hypoxia-induced endothelial tube formation, whereas endothelial cells from mice with haploinsufficiency of KLF2 showed increased tube formation in response to hypoxia. Consistent with this ex vivo observation, KLF2 heterozygous mice showed increased microvessel density in the brain. Mechanistically, KLF2 promoted HIF-1alpha degradation in a von Hippel-Lindau protein-independent but proteasome-dependent manner. Finally, KLF2 disrupted the interaction between HIF-1alpha and its chaperone Hsp90, suggesting that KLF2 promotes degradation of HIF-1alpha by affecting its folding and maturation. These observations identify KLF2 as a novel inhibitor of HIF-1alpha expression and function. Therefore, KLF2 may be a target for modulating the angiogenic response in disease states.
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PMID:Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. 1949 Nov 9

Dominantly inherited mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common cause of familial Parkinson's disease (PD) and have also been identified in individuals with sporadic PD. Although the exact cellular function of LRRK2 remains unknown, most PD-linked mutations appear to be toxic to cells in culture via mechanisms that depend on the kinase activity of LRRK2 or on the formation of cytoplasmic inclusions. Here we show that the E3 ubiquitin ligase CHIP physically associates with LRRK2 and regulates the cellular abundance of LRRK2. We further show that LRRK2 forms a complex with overexpressed and endogenous CHIP and Hsp90. Our data indicates that the destabilization of LRRK2 by CHIP is due to ubiquitination and proteasome-dependent degradation. Hsp90 can attenuate CHIP-mediated degradation and this can be blocked by the Hsp90 inhibitor geldanamycin. These findings provide important insight into the cellular regulation of LRRK2 stability and may lead to the development of therapeutics to treat PD based on controlling LRRK2 stability.
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PMID:Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP. 1953 28

A subset of Eph receptors and their corresponding ligands are commonly expressed in tumor cells where they mediate biological processes such as cell migration and adhesion, whereas their expression in endothelial cells promotes angiogenesis. In particular, the tumor-specific up-regulation of EphA2 confers properties of increased cellular motility, invasiveness, tumor angiogenesis, and tumor progression, and its overexpression correlates with poor prognosis in several cancer types. The cellular chaperone Hsp90 also plays a significant role in regulating cell migration and angiogenesis, although the full repertoire of motility driving proteins dependent on Hsp90 function remain poorly defined. We explored the hypothesis that Hsp90 may regulate the activity of EphA2 and examined the potential relationship between EphA2 receptor signaling and chaperone function. We show that geldanamycin, an Hsp90 antagonist, dramatically destabilizes newly synthesized EphA2 protein and diminishes receptor levels in a proteasome-dependent pathway. In addition, geldanamycin treatment impairs EphA2 signaling, as evidenced by a decrease in ligand-dependent receptor phosphorylation and subsequent cell rounding. Therefore, Hsp90 exerts a dual role in regulating the stability of nascent EphA2 protein and maintaining the signaling capacity of the mature receptor. Our findings also suggest that the geldanamycin-dependent mitigation of EphA2 signaling in receptor-overexpressing cancer cells may be sufficient to recapitulate the antimotility effects of this drug. Finally, the identification of a pharmacologic approach to suppress EphA2 expression and signaling highlights the attractive possibility that Hsp90 inhibitors may have clinical utility in antagonizing EphA2-dependent tumorigenic progression.
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PMID:Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis. 1956 82

Chaperone-enriched domains are formed in the nuclei of cells lytically infected with herpes simplex virus type 1 (HSV-1). These domains, called VICE, for virus induced chaperone enriched, contain Hsc70, Hsp70, Hsp40, Hsp90, polyubiquitinated proteins, and components of the proteasome machinery. Accumulating evidence indicates that these sites may be utilized during infection to sequester misfolded, modified, or otherwise unwanted proteins away from viral replication compartments, sites of robust transcription, DNA synthesis, and capsid maturation. To further explore the role of cellular chaperones and VICE domains during HSV-1 infection, we have analyzed the cytoprotective chaperone Hsp27. Here we present evidence that Hsp27, which is known to possess several antioxidant functions, is rapidly reorganized and modified at early stages in response to HSV-1 infection and signaling from the mitogen-activated protein kinase p38. Immunofluorescence analysis and fractionation experiments reveal disparate subcellular localizations of nonphosphorylated and phosphorylated forms of Hsp27 during wild-type HSV-1 infection. Unmodified forms of Hsp27 are localized in nuclear foci that are outside of replication compartments, adjacent to VICE domains, and in the cytoplasm. Conversely, we find that phosphorylated forms of Hsp27 are localized exclusively in the cytoplasm. Last, in cells depleted of all forms of Hsp27, virus replication is significantly reduced.
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PMID:Modification and reorganization of the cytoprotective cellular chaperone Hsp27 during herpes simplex virus type 1 infection. 1958 60

The molecular chaperone complex Hsp90-p23 interacts with the rate-limiting catalytic subunit of telomerase, hTERT. Although their interactions are required for proper folding of nascent hTERT as well as the assembly of active telomerase, the precise role of the chaperone proteins in regulation of nuclear localization of hTERT remains unclear. Here we demonstrate that curcumin inhibits telomerase activity in a time- and dose-dependent manner by decreasing the level of hTERT expression. Following curcumin treatment, we observed a clear accumulation of hTERT in the cytoplasmic compartment of the cell. The curcumin-induced cytoplasmic retention of hTERT could be due to failure of nuclear import, and the resulting cytoplasmic hTERT protein was rapidly ubiquitinated and degraded by the proteasome. We also report that curcumin treatment results in a substantial decrease in association of p23 and hTERT but does not affect the Hsp90 binding to hTERT. In contrast, the treatment of the Hsp90 inhibitor geldanamycin promotes dissociation of both Hsp90 and p23 proteins from hTERT. Taken together, these results demonstrate that the interaction of the Hsp90-p23 complex with hTERT is critical for regulation of the nuclear localization of telomerase, and that down-regulation of hTERT by curcumin involves dissociating the binding of hTERT with p23. Thus, inhibition of nuclear translocation of hTERT by curcumin may provide new perspectives for regulation of telomerase activity during tumorigenic progression.
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PMID:Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT. 1975 63


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