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)

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90.
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PMID:Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. 1885 23

The ubiquitin proteasome system (UPS) degrades abnormal proteins and most unneeded normal proteins, thereby playing a critical role in protein homeostasis in the cell. Proteasome inhibition is effective in treating certain forms of cancer, while UPS dysfunction is increasingly implicated in the pathogenesis of many severe and yet common diseases. It has been previously shown that doxorubicin (Dox) enhances the degradation of a UPS surrogate substrate in mouse hearts. To address the underlying mechanism, in the present study, we report that 1) Dox not only enhances the degradation of an exogenous UPS reporter (GFPu) but also antagonizes the proteasome inhibitor-induced accumulation of endogenous substrates (e.g., beta-catenin and c-Jun) of the UPS in cultured NIH 3T3 cells and cardiomyocytes; 2) Dox facilitates the in vitro degradation of GFPu and c-Jun by the reconstituted UPS via the enhancement of proteasomal function; 3) Dox at a therapeutically relevant dose directly stimulates the peptidase activities of purified 20S proteasomes; and 4) Dox increases, whereas proteasome inhibition decreases, E3 ligase COOH-terminus of heat shock protein cognate 70 in 3T3 cells via a posttranscriptional mechanism. These new findings suggest that Dox activates the UPS by acting directly on both the ubiquitination apparatus and proteasome.
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PMID:A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome. 1897 87

BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival in a variety of normal and neoplastic cell types, via its interaction with a variety of partners, such as the heat shock protein (HSP) 70, Bcl-2, Raf-1 and others. Expression of BAG3 is induced by some stressful stimuli, such as heat shock, heavy metal exposure. We have reported that proteasome inhibitors can also induce BAG3 expression at the transcriptional level and the induction of BAG3 compromises proteasome inhibitors-mediated apoptosis. However, the molecular mechanism of BAG3 upregulation has not been elucidated. In the current study, we provide evidence that heat shock transcription factor 1 (HSF1) is involved in BAG3 induction by proteasome inhibitor MG132. Using a series of varying lengths of 5'-flanking region of the BAG3 gene into luciferase reporter vectors, we found that MG132 stimulated the promoter activity via the -326/-233 and -825/-689 regions, which contains one putative heat shock-responsive element (HSE) for HSF1-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSF1 directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSF1 occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSF1 by small interfering RNA attenuated the BAG3 upregulation due to MG132.These results indicate that the proteasome inhibitor MG132 induces BAG3 expression through HSF1 activation.
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PMID:Proteasome inhibitor MG132 induces BAG3 expression through activation of heat shock factor 1. 1900 20

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

alpha-Synuclein is the major building block of cytoplasmic inclusions in neurodegenerative disorders named synucleinopathies. These inclusion bodies often contain the small heat shock protein alphaB-crystallin and the microtubule-associated protein tau. Oxidative modification of alpha-synuclein has been linked to fibril formation, and alpha-synuclein aggregation may induce the fibrillization of tau. To study alpha-synuclein aggregate formation, we have engineered oligodendroglial cells (OLN-93 cells) to stably express the longest human isoform of tau and wild-type alpha-synuclein or the A53T alpha-synuclein mutation. Under normal growth conditions, small punctuated alpha-synuclein aggregates were formed, which were more abundant in cells expressing the A53T mutation. After exposure to oxidative stress, protein inclusions were enlarged and were positive for thioflavin S, but the solubility of alpha-synuclein was not altered. Oxidative stress followed by proteasomal inhibition caused the occurrence of larger thioflavin S-positive inclusions, immunoreactive for tau and alphaB-crystallin, thus resembling glial cell inclusion bodies. Furthermore, this double stress situation led to a decrease in alpha-synuclein solubility, and alphaB-crystallin and HSP90 were present in the insoluble fraction. The formation and recruitment of tau to thioflavin S-positive protein aggregates in OLN-93 cells only expressing tau in the absence of alpha-synuclein, either after oxidative or proteasomal stress or both, was not observable. The data indicate that oxidatively modified alpha-synuclein is degraded by the proteasome and that it plays a pro-aggregatory role for tau in this cell culture model system.
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PMID:alpha-Synuclein promotes the recruitment of tau to protein inclusions in oligodendroglial cells: effects of oxidative and proteolytic stress. 1926 22

Overexpression of the human epidermal growth factor receptor 2 (HER-2) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior, and response to systemic therapy. Trastuzumab is a monoclonal antibody directed against HER-2 which has revolutionized the management of both early and advanced breast cancer. It may exert its anti-cancer effects through inhibition of intracellular signaling, upregulation of p27, impaired angiogenesis, induction of immune-mediated destruction, and blockade of cleavage of the extracellular domain of HER-2. In spite of its robust clinical activity, most women with metastatic HER-2 overexpressing breast cancer eventually progress on trastuzumab therapy. Possible mechanisms of resistance include: altered receptor antibody interaction, PTEN loss and enhanced Akt signaling, p27 loss, signaling through other receptors. Preclinical experiments, clinical experience with the use of trastuzumab beyond progression, and a recent phase III clinical trial with Lapatinib, a dual EGFR/HER-2 tyrosine kinase inhibitor, demonstrate that the HER-2 signaling axis remains an important therapeutic target even after progression on trastuzumab. A variety of novel strategies are currently in development to exploit this pathway following the onset of resistance, such as receptor antibodies, sheddase inhibitors, signal transduction inhibitors, heat shock protein inhibitors, proteasome inhibitors, anti-angiogenic agents, and immune-stimulatory therapies, either as single agents or in combination with trastuzumab. Rational clinical trial design, with attention to appropriate patient selection and prospective collection of biological material, is needed to ensure that the new generation of anti-HER-2 targeted therapies realizes its promise in the treatment of trastuzumab-resistant disease.
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PMID:Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. 1927 56

Schistosomiasis is considered the most important human helminthiasis in terms of morbidity and mortality. In this study, comparative soluble proteomic analysis of normal cercariae and ultraviolet-irradiated attenuated cercariae (UVAC) from Schistosoma japonicum were carried out in view of the high efficiency of irradiation-attenuated cercariae vaccine. The results revealed that some proteins showed significant differential expression in the parasite after treatment with ultraviolet light. Total 20 protein spots were identified by mass spectrometry, corresponded to five groups according to their functions in the main that were structural and motor proteins (actin, et al.), energy metabolism associated enzymes (glyceraldehydes-3-phosphage dehydrogenase, et al.), signaling transduction pathway-associated molecules (14-3-3 protein, et al.), heat shock protein families (HSP 70 family, et al.), and other functional proteins (20S proteasome). Furthermore, our results indicated that the differential expression of the proteins by ultraviolet irradiation may be, at least partially, acquired by regulating the mRNA levels of corresponding proteins. These results may provide new clues for further exploring the mechanism of protective immunity induced by UVAC and may shed some light on the development of vaccines against schistosomiasis.
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PMID:Schistosoma japonicum: proteomics analysis of differentially expressed proteins from ultraviolet-attenuated cercariae compared to normal cercariae. 1929 May 41

BAG6/Scythe/Bat3 is a cochaperone of the heat shock protein HSP70 and is involved in various developmental processes, cellular stress and viability. BAG6 interferes with the protein-refolding activity of HSP70 but its precise involvement in proteotoxic stresses remains unknown. We show that BAG6 is required for the accumulation of HSP70 upon heat shock and that conversely, once accumulated, HSP70 leads to the massive and CHIP-independent degradation of BAG6 through the ubiquitin-proteasome system. These reciprocal influences between BAG6 and HSP70 upon heat shock suggest that BAG6 is a central regulator of the cellular content of HSP70. The HSP70-driven degradation of BAG6, following the BAG6-dependent accumulation of HSP70, could allow the protein-refolding activity of HSP70 and limit the extent of its induction.
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PMID:Sequential interplay between BAG6 and HSP70 upon heat shock. 1935 8

The availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms. New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies. The aim of this review is to identify and discuss non-monoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide, mammalian target of rapamycin inhibitors, antisense oligonucleotides, heat shock protein inhibitors, protein kinase C inhibitors, antiangiogenic agents, and new cytotoxics are reviewed.
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PMID:Beyond monoclonal antibodies: new therapeutic agents in non-Hodgkin's lymphomas. 1941 16

Cytochrome P450 2C9 (P450 2C9) is one of the most important P450 isoforms in the human liver, as it metabolizes numerous exogenous and endogenous substrates. Moreover, it is inducible by several compounds, such as rifampicin, phenobarbital, and NSAIDs (nonsteroidal anti-inflammatories). The aim of this study was to investigate the global cellular consequences of P450 2C9 overexpression at the transcriptional level using an untargeted approach: pangenomic microarrays. Recombinant adenovirus was used to express P450 2C9 instead of an inducer to prevent a per se effect of inducer or its metabolites. P450 2C9 overexpression induced endoplasmic reticulum (ER) stress and regulated genes implicated in the unfolded protein response (UPR) as heat shock protein (HSP) (we studied particurlarly HSPA5 and HSPB1) and in the endoplasmic reticulum associated degradation (ERAD) system as Sec61 and ubiquitin and proteasome pathways. UPR and ERAD are two mechanisms of adaptative response to ER stress. Moreover, activation of Akt was observed in HepG2 cells that overexpress P450 2C9 and might participate in the cellular adaptive response to stress, thus leading to the activation of cell survival pathways. UPR and ERAD should be caused by accumulation of native and misfolded P450 2C9 protein. Our results indicated that P450 2C9 overexpression did not lead to toxicity but induced an ER stress due to protein overexpression rather than mono-oxygenase activity. The ER stress triggered activation of the adaptative response and of pathways leading to cell survival.
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PMID:Genomic consequences of cytochrome P450 2C9 overexpression in human hepatoma cells. 1944 31


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