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)

Heat shock proteins (Hsps) facilitate refolding of denatured polypeptides, but there is limited understanding about their roles in neurodegenerative diseases characterized by misfolded proteins. Because Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy are alpha-synucleinopathies characterized by filamentous alpha-synuclein (alpha-syn) inclusions, we assessed which Hsps might be implicated in these disorders by examining human brain samples, transgenic mouse models, and cell culture systems. Light and electron microscopic multiple-label immunohistochemistry showed Hsp90 was the predominant Hsp examined that co-localized with alpha-syn in Lewy bodies, Lewy neurites, and glial cell inclusions and that Hsp90 co-localized with alpha-syn filaments of Lewy bodies in PD. Hsp90 levels were most predominantly increased in PD brains, which correlated with increased levels of insoluble alpha-syn. These alterations in Hsp90 were recapitulated in a transgenic mouse model of PD-like alpha-syn pathologies. Cell culture studies also revealed that alpha-syn co-immunoprecipitated preferentially with Hsp90 and Hsc70 relative to other Hsps, and exposure of cells to proteasome inhibitors resulted in increased levels of Hsp90. These data implicate predominantly Hsp90 in the formation of alpha-syn inclusions in PD and related alpha-synucleinopathies.
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PMID:Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. 1650 10

Heat-shock protein 90 (HSP90) has diverse functions in mammalian cells. It acts as molecular chaperone, together with several co-chaperone molecules (such as Hop, Hip, p23, cdc37, Aha, and immunophilins). HSP90 binds to its client proteins (such as steroid receptors, AKT, Bcr-Abl, Apaf-1, survivin, cyclin dependent kinases which are involved in signal transduction that regulate cell cycle, survival, and death, and promote their proper protein folding, assembly, and transportation across different cellular compartments. Failure of Hsp90 chaperone activity leads to misfolding of client proteins, which leads to ubiquitination and proteasome degradation, and this deregulating cellular homeostasis. Since tumor cells frequently overexpress the active form of HSP90, which is more susceptible to inhibition by small molecules such as geldanamycin and its analogs, HSP90 became an attractive target for cancer therapy. This paper will review the recent advances in HSP90-biology and will discuss the emerging role of the HSP90 inhibitors such as 17-allylamino-17 demethoxy-geldanamycin and other HSP-90-directed small molecules in cancer therapy.
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PMID:Heat-shock protein 90 inhibitors in cancer therapy: 17AAG and beyond. 1655 99

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.
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PMID:Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. 1661 63

CHIP proteins are E3 ubiquitin ligases that promote degradation of Hsp70 and Hsp90 substrate proteins through the 26S proteasome in animal systems. A CHIP-like protein in Arabidopsis, AtCHIP, also has E3 ubiquitin ligase activity and has important roles to play under conditions of abiotic stress. In an effort to study the mode of action of AtCHIP in plant cells, proteins that physically interact with it were identified. Like its animal orthologs, AtCHIP interacts with a unique class of ubiquitin-conjugating enzymes (UBC or E2) that belongs to the stress-inducible UBC4/5 class in yeast. AtCHIP also interacts with other proteins, including an A subunit of protein phosphatase 2A (PP2A). This PP2A subunit appears to be a substrate of AtCHIP, because it can be ubiquitylated by AtCHIP in vitro and because the activity of PP2A is increased in AtCHIP-overexpressing plants in the dark or under low-temperature conditions. Unlike the rcn1 mutant, that has reduced PP2A activity due to a mutation in one of the A subunit genes of PP2A, AtCHIP-overexpressing plants are more sensitive to ABA treatment. Since PP2A was previously shown to be involved in low-temperature responses in plants, the low-temperature-sensitive phenotype observed in AtCHIP-overexpressing plants might be partly due to the change in PP2A activity. These data suggest that the E3 ubiquitin ligase AtCHIP may function upstream of PP2A in stress-responsive signal transduction pathways under conditions of low temperature or in the dark.
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PMID:AtCHIP functions as an E3 ubiquitin ligase of protein phosphatase 2A subunits and alters plant response to abscisic acid treatment. 1664 Jun 1

The past two decades have seen a dramatic change in cancer treatment paradigms. Anticancer agents are no longer being developed based on empiricism and serendipity, but are now being aimed to inhibit a validated target that is relatively specific for tumours rather than normal cells. The vast majority of cancers arise from multiple genetic lesions; thus, sophisticated drug cocktails, or single drugs acting on multiple downstream targets will be needed for successful cancer therapy. Three emerging concepts that are addressing these therapeutic needs and that are key to blocking steps in tumourigenesis will be highlighted in this review: (a) attacking cancer cell immortality by targeting the telomere/telomerase complex; (b) targeting oncogene activation by inhibiting the molecular chaperone Hsp90; and (c) stabilizing tumour suppressor proteins by modulating the ubiquitin-proteasome system.
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PMID:Highlights in experimental therapeutics. 1664

We have previously shown that the proteasome activator PA28 is essential to Hsp90-dependent protein refolding in vitro, where PA28 mediates transfer of the Hsp90-bound substrate protein to the Hsc70/Hsp40 chaperone machine for its correct refolding. This observation suggests that PA28 may also collaborate with Hsp90 in cells. To examine this possibility, here we have used double-stranded RNA interference (RNAi) against PA28 in Caenorhabditis elegans mutants of daf-21, which encodes Hsp90. We show that C. elegans PA28 facilitates Hsp90-initiated protein refolding, albeit with an activity lower than that of mouse PA28 proteins. RNAi-mediated knockdown of PA28 significantly suppresses the Daf-c (dauer formation constitutive) phenotype of the daf-21 mutant, but it has no affect on the distinct defects of this mutant in sensing odorants. Taking these results together, we conclude that PA28 is likely to function in collaboration with Hsp90 in vivo.
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PMID:The proteasome activator PA28 functions in collaboration with Hsp90 in vivo. 1665 Aug 28

Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.
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PMID:Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. 1674 51

The selectivity underlying the recognition of oxidized calmodulin (CaM) by the 20S proteasome in complex with Hsp90 was identified using mass spectrometry. We find that degradation of oxidized CaM (CaMox) occurs in a multistep process, which involves an initial cleavage that releases a large N-terminal fragment (A1-F92) as well as multiple smaller carboxyl-terminus peptides ranging from 17 to 26 amino acids in length. These latter small peptides are enriched in methionine sulfoxides (MetO), suggesting a preferential degradation around MetO within the carboxyl-terminal domain. To confirm the specificity of CaMox degradation and to identify the structural signals underlying the preferential recognition and degradation by the proteasome/Hsp90, we have investigated how the oxidation of individual methionines affect the degradation of CaM using mutants in which all but selected methionines in CaM were substituted with leucines. Substitution of all methionines with leucines except Met144 and Met145 has no detectable effect on the structure of CaM, permitting a determination of how site-specific substitutions and the oxidation of Met144 and Met145 affects the recognition and degradation of CaM by the proteasome/Hsp90. Comparable rates of degradation are observed upon the selective oxidation of Met144 and Met145 in CaM-L7 relative to that observed upon oxidation of all nine methionines in wild-type CaM. Substitution of leucines for either Met144 or Met145 promotes a limited recognition and degradation by the proteasome that correlates with decreases in the helical content of CaM. The specific oxidation of Met144 has little effect on rates of proteolytic degradation by the proteasome/Hsp90 or the structure of CaM. In contrast, the specific oxidation of Met145 results in both large increases in the rate of degradation by the proteasome/Hsp90 and significant circular dichroic spectral shape changes that are indicative of changes in tertiary rather than secondary structure. Thus, tertiary structural changes resulting from the site-specific oxidation of a single methionine (i.e., Met145) promote the degradation of CaM by the proteasome/Hsp90, suggesting a mechanism to regulate cellular metabolism through the targeted modulation of CaM abundance in response to oxidative stress.
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PMID:Tertiary structural rearrangements upon oxidation of Methionine145 in calmodulin promotes targeted proteasomal degradation. 1675 Dec 45

Aggresomes have been described as cytoplasmic membrane protein aggregates that are induced by proteasome inhibition or overexpression of certain proteins. Here, we characterized aggresomes formed by the Alzheimer's disease-associated presenilin 1 (PS1) protein. Proteasome inhibition induced accumulation of PS1 in the endoplasmic reticulum (ER) and retrotranslocation of the protein from the ER membrane into the cytoplasm. Aggresomes formed by PS1 modified the ER structure whereas proteasomes were inhibited. Therefore, clear visual identification of PS1 aggresomes required removal of the proteasome inhibitor followed by hours of recovery to redistribute the ER throughout the cells. Aggresomes formed by PS1 did not potentiate or attenuate apoptotic cell death induced by staurosporine treatment. Selective presence of the heat-shock proteins Hsp70 and HDJ-2/HSDJ, but not Hsp90, in aggresomes suggested chaperone-mediated transport of PS1 into these structures. Because proteasome inhibition and heat shock are both known to induce expression of heat shock proteins, we also demonstrated that heat shock alone was sufficient to induce PS1 aggresome formation and Hsp70 expression. These results indicate that aggresome formation by PS1 is chaperone-mediated and can be induced in response to heat-shock stress, a common cellular event in neurodegenerative diseases. Malfunctioning of the proteasome or heat-shock stress response in the brains of patients affected by Alzheimer's disease may lead to the accumulation of stable aggresomes of PS1, perhaps contributing to neurodegeneration.
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PMID:Presenilin 1 forms aggresomal deposits in response to heat shock. 1675 5

Breast cancer metastasis suppressor 1 (BRMS1) is a member of the mSin3-HDAC transcription co-repressor complex. However, the proteins associated with BRMS1 have not been fully identified. Yeast two-hybrid screen, immuno-affinity chromatography, and co-immunoprecipitation experiments were performed to identify BRMS1 interacting proteins (BIPs). In addition to known core mSin3 transcriptional complex components RBBP1 and mSDS3, BRMS1 interacted with other proteins including three chaperones: DNAJB6 (MRJ), Hsp90, and Hsp70. Hsp90 is a known target of HDAC6 and reversible acetylation is one of the mechanisms that is implicated in regulation of Hsp90 chaperone complex activity. BRMS1 interacted with class II HDACs, HDAC 4, 5, and 6. We further found that BRMS1 is stabilized by Hsp90, and its turnover is proteasome dependent. The stability of BRMS1 protein may be important in maintaining the functional role of BRMS1 in metastasis suppression.
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PMID:Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone. 1691 37


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