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)

A major challenge to broadening oncology applications for inhibitors of the ubiquitin-proteasome system (UPS) is the identification of UPS-dependent cancer pathways predictive of tumors responsive to peptidomimetic inhibitors of its 20S core protease activity. To inform clinical studies evaluating UPS inhibitors as breast cancer therapeutics, seven phenotypically diverse human breast cancer cell line models were characterized for their cellular and molecular responses to the clinically approved 20S inhibitor bortezomib (PS341; Velcade), focusing on those overexpressing estrogen receptor (ER) or ERBB2/HER2, because these oncogenic receptor pathways are constitutively activated in approximately 80% of all breast cancers. All models demonstrated dose-dependent bortezomib reduction in intracellular 20S activity correlating with cell growth inhibition, and bortezomib IC(50) values (concentrations producing 50% growth inhibition) varied directly with pretreatment 20S activities (r = 0.74; *, p < 0.05), suggesting that basal 20S activity may serve as a clinical predictor of tumor responsiveness to UPS inhibition. Reduction in 20S activity (> 60%) was associated with early (24 h) intracellular relocalization of ER (nucleus to cytoplasm) and ERBB2 (plasma membrane to perinuclear lysosomes), buildup of ubiquitinated and Hsp70-associated receptor, degradation and loss of ER and ERBB2 function, and induction of cellular apoptosis. These models were also used to screen a pharmacologic panel of pathway-targeted anticancer agents [4-hydroxy-3-methoxy-5-(benzothiazolylthiomethyl)benzylidenecyanoacetamide (AG825), 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (AZD6244/ARRY142886), 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride (LY294002), 17-N-allylamino-17-demethoxy geldanamycin (17AAG), and (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (LAQ824)] for those capable of sensitizing to bortezomib. In keeping with the observation that 20S reduction has little effect on mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling in either ER-positive or ERBB2-positive models, only the MEK-1/2 inhibitor AZD6244 consistently improved the antitumor activity of bortezomib.
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PMID:Proteasome-regulated ERBB2 and estrogen receptor pathways in breast cancer. 1739 24

In mammals, matured oocytes are arrested at the MII stage until fertilization, which is regulated by cytostaticfactor (CSF) activity. Maturation-promoting factor (MPF) and the mitogen-activated protein kinase (MAPK) pathway are known as candidates for CSF. Despite of the results that nuclear and perinuclear materials were dispensable for activation of MPF and MAPK in other species, our previous study in rats demonstrated that MPF activity was rapidly decreased after enucleation. We showed here for the first time that nuclear and perinuclear materials were indispensable for CSF activity in matured rat oocytes. In both cytoplasm-removed and enucleated oocytes, high activity of p34(cdc2) kinase was observed immediately after manipulation, but the activity of enucleated oocytes was dramatically reduced within 1 h. Cyclin B level was also decreased, corresponding with inactivation of p34(cdc2) kinase. In enucleated oocytes, the Mos level was dramatically decreased, and both MEK and MAPK dephosphorylation were also induced. A combined treatment with a proteasome inhibitor, MG132, and a protein phosphatase inhibitor, okadaic acid, dramatically improved both levels of p-MAPK and cyclin B in these enucleated oocytes. These data suggest that nuclear and perinuclear materials of matured rat oocytes suppress proteasome and protein phosphatase activation, which is indispensable for stability of CSF.
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PMID:Effect of enucleation on inactivation of cytostatic factor activity in matured rat oocytes. 1757 58

The last decade has witnessed the introduction of a large number of novel, molecularly targeted agents into the therapeutic armamentarium against diverse forms of cancer, including leukemia. Such agents include signal transduction, cell cycle, histone deacetylase, Hsp90, proteasome, and Bcl-2 family member inhibitors, among others. While most of these agents have been or are currently being evaluated in adult patients with acute leukemia, experience in childhood leukemia is very limited. Although the use of such targeted agents as potentiators of conventional cytotoxic agent activity represents a logical approach, an emerging body of evidence suggests that neoplastic cells in general, and leukemic cells in particular, are highly susceptible to a therapeutic strategy in which survival signaling and cell cycle regulatory pathways are simultaneously disrupted. In in vitro studies, highly synergistic antileukemic interactions have been reported between CDK and HDAC inhibitors; HDAC and proteasome inhibitors; Bcl-2 antagonists and CDK inhibitors; MEK/ERK and Chk1 inhibitors, and proteasome and CDK inhibitors, among other combinations. Some of these strategies, including combinations of HDAC and CDK inhibitors, and CDK and proteasome inhibitors, have now entered the clinical arena in patients with leukemia and other hematologic malignancies. Based upon preclinical results to date, there is reason to suspect that such strategies might prove to be active against several types of childhood leukemia. Thus, over the next decade, the introduction of molecularly targeted agents, alone and in combination, into the therapeutic armamentarium against childhood leukemia may have significant implications for children with this disease.
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PMID:Simultaneous interruption of signal transduction and cell cycle regulatory pathways: implications for new approaches to the treatment of childhood leukemias. 1758 30

Many bacteria pathogenic for plants or animals, including Shigella spp., which is responsible for shigellosis in humans, use a type III secretion apparatus to inject effector proteins into host cells. Effectors alter cell signaling and host responses induced upon infection; however, their precise biochemical activities have been elucidated in very few cases. Utilizing Saccharomyces cerevisiae as a surrogate host, we show that the Shigella effector IpaH9.8 interrupts pheromone response signaling by promoting the proteasome-dependent destruction of the MAPKK Ste7. In vitro, IpaH9.8 displayed ubiquitin ligase activity toward ubiquitin and Ste7. Replacement of a Cys residue that is invariant among IpaH homologs of plant and animal pathogens abolished the ubiquitin ligase activity of IpaH9.8. We also present evidence that the IpaH homolog SspH1 from Salmonella enterica can ubiquitinate ubiquitin and PKN1, a previously identified SspH1 interaction partner. This study assigns a function for IpaH family members as E3 ubiquitin ligases.
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PMID:Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. 1800 83

Determining the underlying mechanisms of macrophage colony-stimulating factor (M-CSF)-mediated osteoclast survival may be important in identifying novel approaches for treating excessive bone loss. This study investigates M-CSF-mediated MEK/ERK activation and identifies a downstream effector of this pathway. M-CSF activates MEK/ERK and induces MEK-dependent expression of the immediate early gene Egr2. Inhibition of either MEK1/2 or inhibition of Egr2 increases osteoclast apoptosis. In contrast, wild-type Egr2 or an Egr2 point mutant unable to bind the endogenous repressors Nab1/2 (caEgr2) suppresses basal osteoclast apoptosis and rescues osteoclasts from apoptosis induced by MEK1/2 or Egr2 inhibition. Mechanistically, Egr2 induces pro-survival Blc2 family member Mcl1 while stimulating proteasome-mediated degradation of pro-apoptotic Bim. In addition, Egr2 increased the expression of c-Cbl, the E3 ubiquitin ligase that catalyzes Bim ubiquitination. M-CSF, therefore, promotes osteoclast survival through MEK/ERK-dependent induction of Egr2 to control the Mcl1/Bim ratio, documenting a novel function of Egr2 in promoting survival.
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PMID:Novel pro-survival functions of the Kruppel-like transcription factor Egr2 in promotion of macrophage colony-stimulating factor-mediated osteoclast survival downstream of the MEK/ERK pathway. 1819 76

Macrophages from certain inbred mouse strains are rapidly killed (< 90 min) by anthrax lethal toxin (LT). LT cleaves cytoplasmic MEK proteins at 20 min and induces caspase-1 activation in sensitive macrophages at 50-60 min, but the mechanism of LT-induced death is unknown. Proteasome inhibitors block LT-mediated caspase-1 activation and can protect against cell death, indicating that the degradation of at least one cellular protein is required for LT-mediated cell death. Proteins can be degraded by the proteasome via the N-end rule, in which a protein's stability is determined by its N-terminal residue. Using amino acid derivatives that act as inhibitors of this pathway, we show that the N-end rule is required for LT-mediated caspase-1 activation and cell death. We also found that bestatin methyl ester, an aminopeptidase inhibitor protects against LT in vitro and in vivo and that the different inhibitors of the protein degradation pathway act synergistically in protecting against LT. We identify c-IAP1, a mammalian member of the inhibitor of apoptosis protein (IAP) family, as a novel N-end rule substrate degraded in macrophages treated with LT. We also show that LT-induced c-IAP1 degradation is independent of the IAP-antagonizing proteins Smac/DIABLO and Omi/HtrA2, but dependent on caspases.
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PMID:Killing of macrophages by anthrax lethal toxin: involvement of the N-end rule pathway. 1826 92

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates numerous physiological functions. Inhibition of CaMKII activity, mostly by synthetic reagents, has been proved to suppress cell growth in many cases. So far there are no reports about the physiological functions and underlying mechanisms of endogenous CaMKII inhibitory proteins in cell cycle progression. Here we report the characterization of a novel human endogenous CaMKII inhibitor, human CaMKII inhibitory protein alpha (hCaMKIINalpha), which directly interacts with activated CaMKII and effectively inhibits CaMKII activity. hCaMKIINalpha expression is negatively correlated with the severity of human colon adenocarcinoma. Overexpression of hCaMKIINalpha inhibits colon adenocarcinoma growth in vitro and in vivo by arresting the cell cycle at the S phase through its conserved inhibitory region (27CIR), whereas silencing the hCaMKIINalpha expression accelerates tumor growth and cell cycle progression. We found that the effect of hCaMKIINalpha on cell cycle is correlated with up-regulation of p27 expression, which may be due to the inhibition of proteasome degradation, but not transcriptional regulation, of p27. Moreover, hCaMKIINalpha deactivated MEK/ERK, which is prerequisite to the inhibition of Thr-187 phosphorylation and subsequent proteasomal degradation of p27, causing the inhibition of S-phase progression of cell cycle. The findings underscore a link between hCaMKIINalpha-mediated inhibition of CaMKII activity and p27-dependent pathways in controlling tumor cell growth and cell cycle and imply a potential application of hCaMKIINalpha in the therapeutics of colon cancers.
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PMID:A novel endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest via p27 stabilization. 3259 54

This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 microM, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene.
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PMID:MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. 1839 2

Somatic activating mutations of BRAF are the earliest and most common genetic abnormality detected in the genesis of human melanoma. However, the mechanism(s) by which activated BRAF promotes melanoma cell cycle progression and/or survival remain unclear. Here we demonstrate that expression of BIM, a pro-apoptotic member of the BCL-2 family, is inhibited by BRAF-->MEK-->ERK signaling in mouse and human melanocytes and in human melanoma cells. Trophic factor deprivation of melanocytes leads to elevated BIM expression. However, re-addition of trophic factors or activation of a conditional form of BRAF(V600E) leads to rapid inhibition of BIM expression. In both cases, inhibition of BIM expression was dependent on the activity of MEK1/2 and the proteasome. Consistent with these observations, pharmacological inhibition of BRAF(V600E) or MEK1/2 in human melanoma cells (using PLX4720 and CI-1040 respectively) led to a striking elevation of BIM expression. Re-activation of BRAF-->MEK-->ERK signaling led to phosphorylation of BIM-EL on serine 69 and its subsequent degradation. Interestingly, endogenous expression of BIM in melanoma cells was insufficient to induce apoptosis unless combined with serum deprivation. Under these circumstances, inhibition of BIM expression by RNA interference provided partial protection from apoptosis. These data suggest that regulation of BIM expression by BRAF-->MEK-->ERK signaling is one mechanism by which oncogenic BRAF(V600E) can influence the aberrant physiology of melanoma cells.
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PMID:Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival. 1871 33

Lipopolysaccharide (LPS), a glycolipid component of the outer membrane of Gram-negative bacteria, is a potent initiator of the innate immune response of the macrophage. LPS triggers downstream signaling by selectively recruiting and activating proteins in cholesterol-rich membrane microdomains called lipid rafts. We applied proteomics analysis to macrophage detergent-resistant membranes (DRMs) during an LPS exposure time course in an effort to identify and validate novel events occurring in macrophage rafts. Following metabolic incorporation in cell culture of heavy isotopes of amino acids arginine and lysine ([(13)C(6)]Arg and [(13)C(6)]Lys) or their light counterparts, a SILAC (stable isotope labeling with amino acids in cell culture)-based quantitative, liquid chromatography-tandem mass spectrometry proteomics approach was used to profile LPS-induced changes in the lipid raft proteome of RAW 264.7 macrophages. Unsupervised network analysis of the proteomics data set revealed a marked representation of the ubiquitin-proteasome system as well as changes in proteasome subunit composition following LPS challenge. Functional analysis of DRMs confirmed that LPS causes selective activation of the proteasome in macrophage rafts and proteasome inactivation outside of rafts. Given previous reports of an essential role for proteasomal degradation of IkappaB kinase-phosphorylated p105 in LPS activation of ERK mitogen-activated protein kinase, we tested for a role of rafts in compartmentalization of these events. Immunoblotting of DRMs revealed proteasome-dependent activation of MEK and ERK specifically occurring in lipid rafts as well as proteasomal activity upon raft-localized p105 that was enhanced by LPS. Cholesterol extraction from the intact macrophage with methyl-beta-cyclodextrin was sufficient to activate ERK, recapitulating the LPS-IkappaB kinase-p105-MEK-ERK cascade, whereas both it and the alternate raft-disrupting agent nystatin blocked subsequent LPS activation of the ERK cascade. Taken together, our findings indicate a critical, selective role for raft compartmentalization and regulation of proteasome activity in activation of the MEK-ERK pathway.
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PMID:Quantitative proteomics analysis of macrophage rafts reveals compartmentalized activation of the proteasome and of proteasome-mediated ERK activation in response to lipopolysaccharide. 1881 23


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