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)

Several important signaling proteins including transcription factors and protein kinases depend on heat shock protein (Hsp)-90 for stability. p210bcr-abl, a protein expressed in chronic myelogenous leukemia, is functionally inhibited by the benzoquinone ansamycin herbimycin A. Benzoquinone ansamycins also bind to and inhibit the activity of Hsp90. We now demonstrate that p210bcr-abl is complexed with Hsp90 and its cochaperone p23 in K562 chronic myelogenous leukemia cells. Brief exposure to the benzoquinone ansamycin Hsp90 inhibitor geldanamycin (GA) decreases the association of p210bcr-abl with Hsp90 and p23 and increases its association with the chaperones Hsp70 and p60Hop. GA has a similar effect on chaperone association with v-src, another Hsp90-dependent oncogenic kinase. Loss of Hsp90/p23 association and acquisition of Hsp70/p60Hop association of both p210bcr-abl and v-src precede GA-induced degradation of these kinases. GA-induced degradation is mediated by the proteasome because proteasome inhibitors block the effects of GA, causing both p210bcr-abl and v-src to accumulate in a detergent-insoluble cellular fraction. Both p210bcr-abl and v-src are more susceptible to GA-induced degradation than are their normal cellular counterparts, c-abl and c-src.
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PMID:The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. 1093 89

We have previously shown that Epstein-Barr virus (EBV)-encoded EBNA-5 is localized to PML bodies (PODs) in EBV-immortalized lymphoblastoid cell lines (LCLs). Here we have extended our study of the subnuclear localization of EBNA-5 and found a strict co-localization with PML in LCLs and in BL lines with an immunoblastic, LCL-like phenotype. Moreover, GFP-EBNA-5 accumulated in PML bodies upon transfection into LCLs. In contrast, transfection of cell lines of non-immunoblastic origin with an EBNA-5 expression construct showed preferential localization of the protein to the nucleoplasm. Since PML is involved in proteasome-dependent protein degradation, we investigated the total levels and sub-cellular localization of EBNA-5 upon inhibition of proteasome activity. We found that a proteasome inhibitor, MG132, induced the translocation of both endogenous and transfected EBNA-5 to the nucleoli in every cell line tested. The total EBNA-5 protein levels were not affected by the proteasomal block. EBNA-5 forms complexes with heat shock protein Hsp70. The proteasome inhibitor induced a rise in total levels of Hsp70 and dramatically changed its homogeneous nuclear and cytoplasmic distribution into nucleolar and cytoplasmic. This effect was EBNA-5-independent. The nucleolar localization of Hsp70 was enhanced by the presence of EBNA-5, however. EBNA-5 also enhanced the nucleolar translocation of a mutant p53 in a colon cancer line, SW480, treated with MG132. The coordinated changes in EBNA-5 and Hsp70 localization and the effect of EBNA-5 on mutant p53 distribution upon MG132 treatment might reflect the involvement of EBNA-5 in the regulation of intracellular protein trafficking associated with the proteasome-mediated degradation.
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PMID:Proteasome inhibitor induces nucleolar translocation of Epstein-Barr virus-encoded EBNA-5. 1116 Dec 73

alphaB-Crystallin, a member of the small heat shock protein (sHsp) family, can bind unfolding proteins, but is unable to refold them. To fulfil its protective function in vivo it is therefore likely to interact with other cellular proteins. Here we report that alphaB-crystallin binds very specifically both in vitro and in vivo to C8/alpha7, one of the 14 subunits of the 20S proteasome. The C8/alpha7 protein forms heterogeneous complexes with alphaB-crystallin of about 540 kDa. However, no strong interaction between alphaB-crystallin and 20S proteasomes was observed. Since both proteins are localized in the cytoplasm, the interaction between alphaB-crystallin and C8/alpha7 subunit might affect the assembly of the proteasome complex or facilitate the degradation of unfolded proteins bound to alphaB-crystallin.
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PMID:Interaction between alphaB-crystallin and the human 20S proteasomal subunit C8/alpha7. 1134 40

Recent studies have demonstrated that inhibition of the proteasome, an enzyme responsible for the majority of intracellular proteolysis, may contribute to the toxicity associated with oxidative stress. In the present study we demonstrate that exposure to oxidative injury (paraquat, H(2)O(2), FeSO(4)) induces a rapid increase in reactive oxygen species (ROS), loss of mitochondrial membrane potential, inhibition of proteasome activity, and induction of cell death in neural SH-SY5Y cells. Application of proteasome inhibitors (MG115, epoxomycin) mimicked the effects of oxidative stressors on mitochondrial membrane potential and cell viability, and increased vulnerability to oxidative injury. Neural SH-SY5Y cells stably transfected with human HDJ-1, a member of the heat shock protein family, were more resistant to the cytotoxicity associated with oxidative stressors. Cells expressing increased levels of HDJ-1 displayed similar degrees of ROS formation following oxidative stressors, but demonstrated a greater preservation of mitochondrial function and proteasomal activity following oxidative injury. Cells transfected with HDJ-1 were also more resistant to the toxicity associated with proteasome inhibitor application. These data support a possible role for proteasome inhibition in the toxicity of oxidative stress, and suggest heat shock proteins may confer resistance to oxidative stress, by preserving proteasome function and attenuating the toxicity of proteasome inhibition.
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PMID:Proteasome inhibition in oxidative stress neurotoxicity: implications for heat shock proteins. 1135 66

The heat shock proteins (HSPs) are molecular chaperones that are emerging as biochemical regulators of cell growth, apoptosis, protein homeostasis and intracellular targeting of peptides. The immunological function of the HSPs are imparted by tissue specific peptides associated with the HSPs and as such autologous cancer derived HSP-peptide complexes are unique therapeutic agents. Since a majority of the intracellular peptides are generated by the proteasome, we examined the consequence of abrogation of proteasome function by proteasome inhibitors (PIs) such as Lactacystin, MG-132 and LLM on the growth and induction profile of HSP70 and gp96 using hematopoietic, lymphoid, and epithelial derived cancer cell lines. The effect on growth was measured by the XTT assay and induction of the heat shock proteins by western blot analyses using HSP70 and gp96 specific antibodies. Of the PIs tested, cancer cells, were most sensitive to MG-132 and least sensitive to LLM. MG-132 also showed a 10-fold differential sensitivity between estrogen receptor positive, (ER+) MCF-7 cells and negative cells, (ER-) MDA-MB-231. Induction of heat shock proteins, gp96 and HSP70 was, however, noted in response to LLM. Since LLM exhibited minimal cytotoxic effect, metabolic stress that results in induction of HSPs may not be translated in cell growth inhibition and that there may exist a cell-type specific phenomenon in the HSP response to PI mediated metabolic stress.
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PMID:Proteasome inhibitors differentially affect heat shock protein response in cancer cells. 1156 76

In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.
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PMID:Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells. 1189 5

The estrogen receptor (ER) is a hormone-dependent transcription factor that belongs to the steroid/thyroid hormone receptor superfamily. Since the ER contributes to development and progression in human breast cancer, a number of studies have explored ways to inactivate this receptor. Previous studies have suggested that the 90-kDa heat shock protein (Hsp90) interacts with the ER, thus stabilizing the receptor in an inactive state. Here, we report that radicicol, an Hsp90-specific inhibitor, repressed estrogen-dependent transactivation of the ER as measured by pS2 gene transcription and a reporter gene encoding an estrogen-responsive element. Furthermore, we showed that radicicol induced rapid degradation of ERalpha, while the amount of ubiquitinated ERalpha was increased. A proteasome inhibitor, LLnL, almost completely abrogated the radicicol-induced decrease in expression level, as well as in transcriptional activity of ERalpha. These results suggest that radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ERalpha that is susceptible to ubiquitin/proteasome-induced degradation.
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PMID:Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90. 1191 45

Proteasomes are large multimeric self-compartmentizing proteases, which play a crucial role in the clearance of misfolded proteins, breakdown of regulatory proteins, processing of proteins by specific partial proteolysis, cell cycle control as well as preparation of peptides for immune presentation. Two main types can be distinguished by their different tertiary structure: the 20S proteasome and the proteasome-like heat shock protein encoded by heat shock locus V, hslV. Usually, each biological kingdom is characterized by its specific type of proteasome. The 20S proteasomes occur in eukarya and archaea whereas hslV protease is prevalent in bacteria. To verify this rule we applied a genome-wide sequence search to identify proteasomal sequences in data of finished and yet unfinished genome projects. We found several exceptions to this paradigm: (1) Protista: in addition to the 20S proteasome, Leishmania, Trypanosoma and Plasmodium contained hslV, which may have been acquired from an alpha-proteobacterial progenitor of mitochondria. (2) Bacteria: for Magnetospirillum magnetotacticum and Enterococcus faecium we found that each contained two distinct hslVs due to gene duplication or horizontal transfer. Including unassembled data into the analyses we confirmed that a number of bacterial genomes do not contain any proteasomal sequence due to gene loss. (3) High G+C Gram-positives: we confirmed that high G+C Gram-positives possess 20S proteasomes rather than hslV proteases. The core of the 20S proteasome consists of two distinct main types of homologous monomers, alpha and beta, which differentiated into seven subtypes by further gene duplications. By looking at the genome of the intracellular pathogen Encephalitozoon cuniculi we were able to show that differentiation of beta-type subunits into different subtypes occurred earlier than that of alpha-subunits. Additionally, our search strategy had an important methodological consequence: a comprehensive sequence search for a particular protein should also include the raw sequence data when possible because proteins might be missed in the completed assembled genome. The structure-based multiple proteasomal alignment of 433 sequences from 143 organisms can be downloaded from the URL dagger and will be updated regularly.
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PMID:A comprehensive view on proteasomal sequences: implications for the evolution of the proteasome. 1259 56

Molecular chaperones participate in folding of many proteins and several families are known to exist in mammalian cells including the small heat shock protein (sHSP) family. sHSPs have a molecular mass of 15-30 kDa and are known to be induced and phosphorylated in response to various stimuli. There are several reports describing the correlation between sHSPs and degenerative diseases. We have been reported that Hsp27 and alpha B-crystallin were recruited to aggresome when cells were treated with proteasome inhibitors. Expression of Hsp27 suppresses the cell death induced by expression of expanded polyglutamine via down regulation of the oxidative stress pathway. Recently, a missense mutation in alpha B-crystallin, R120G, has been found in a French family suffering from desmin-related myopathy. Moreover, transgenic mice expressing R120G alpha B-crystallin exhibit symptoms similar to desmin-related myopathy. We recently examined the interaction of R120G alpha B-crystallin and Hsp27 in mammalian cells and found that expression of R120G alpha B-crystallin caused formation of inclusion bodies and co-expression of Hsp27 inhibited this formation of inclusion bodies. Clarification of physiological roles of sHSPs in degenerative diseases may lead to the development of new therapy.
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PMID:[Small heat shock proteins participate in the regulation of cellular aggregates of misfolded protein]. 1261 35

Although the proteasome plays a critical role in the controlled degradation of proteins involved in cell cycle control, the direct modulation of proteasomal function by growth regulatory signaling has not yet been demonstrated. We assessed the effect of transforming growth factor (TGF)-beta, a potent inhibitor of cell growth, on proteasomal function. TGF-beta selectively decreased hydrolysis of the proteasomal substrate Cbz-Leu-Leu-Leu-7-amido-4-methyl-coumarin (z-LLL-AMC) in a concentration-dependent manner but did not inhibit hydrolysis of other substrates Suc-Leu-Leu-Val-Tyr-AMC (suc-LLVY-AMC) or Cbz-Leu-Leu-Glu-AMC (z-LLE-AMC). An increase in intracellular oxidative injury occurred during incubation with TGF-beta. Furthermore, in vitro hydrolysis of z-LLL-AMC, but not suc-LLVY-AMC, was decreased by hydrogen peroxide. TGF-beta did not increase cellular expression of heat shock protein (HSP)90, a potent inhibitor of z-LLL-AMC hydrolysis in vitro. The physiological relevance of TGF-beta inhibition of proteasomal activity was studied by assessing the role of z-LLL-AMC hydrolysis on cyclin-dependent kinase inhibitor expression and cell growth. TGF-beta increased expression of p27KIP1 but did not alter expression of p21WAF1 or p16INK4A. The peptide aldehyde Cbz-Leu-Leu-leucinal (LLL-CHO or MG132) potently inhibited z-LLL-AMC hydrolysis in cell extracts as well as increasing p27KIP1 and decreasing cell proliferation. Thus growth inhibition by TGF-beta decreases a specific proteasomal activity via an HSP90-independent mechanism that may involve oxidative inactivation or modulation of proteasomal subunit composition and results in altered cellular expression of key cell cycle regulatory proteins such as p27KIP1.
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PMID:Transforming growth factor-beta inhibition of proteasomal activity: a potential mechanism of growth arrest. 1264 15


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