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 cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line-dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol 3'-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments.
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PMID:Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells. 1654 81

Lung cancer continues to be a leading cause of death in the US, and in its most advanced stages remains incurable. Cytotoxic chemotherapies have been the standard of care for the treatment of unresectable disease. However, recent advances in the development of epidermal growth factor receptor (EGFR) inhibitors have led the way to a new generation of targeted biological agents. During the second annual symposium entitled 'the future of lung cancer: a translational focus', which was sponsored by the Physician s Education Resource, new strategies for the treatment of lung cancer were discussed. Besides the role of EGFR inhibitors, potential targets include the angiogenesis pathway; other growth factor pathways, such as phosphoinositol-3 kinase/Akt and Raf-MEK; the 26S proteasome, the histone deacetylase mechanism; and the TNF-related apoptosis-inducing factor receptors. Agents that are directed against these targets are all in varying stages of clinical development. As more is learned about their mechanisms of action and clinical spectrum of activity, the author anticipates their incorporation into novel regimens with enhanced activity against lung cancer.
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PMID:The second annual symposium on the future of lung cancer: a translational focus. 11-12 November 2005, Washington D.C., USA. 1670 87

Allergic asthma and allergic dermatitis are chronic inflammatory diseases and are characterized by an accumulation of eosinophils at sites of inflammation. Eotaxin-1/CCL11 and eotaxin-3/CCL26 are members of the CC chemokine family, which are known to be potent chemoattractants for eosinophils. We observed that a human lung fibroblast, HFL-1 produces eotaxin-1 and -3 in response to TNF-alpha plus IL-4 stimulation, accompanied with NF-kappaB and STAT6 activation. We explored which signaling pathways are operative in the production of eotaxin-1 and -3 using several inhibitors. Eotaxin-1/CCL11 production was inhibited by a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, but not by the MEK (MAPK/ERK kinase) inhibitors, PD98059 and U0126. In contrast, eotaxin-3/CCL26 production was inhibited similarly by PD98059 as well as U0126 and SB203580. In addition, two proteasome inhibitors, N-acetyl-leucyl-leucyl-norleucinal (ALLN) and bortezomib with significant inhibitory activity on NF-kappaB activation, inhibited eotaxin-1/CCL11 production with IC50 8 microM for ALLN and IC50 16 nM for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10 microM of ALLN (IC50 16 microM) and up to 10 nM of bortezomib (IC50 11 nM), giving inhibition of eotaxin-3/CCL26 less sensitive than eotaxin-1/CCL11 production by the proteasome inhibitors. Synergistic inhibition was observed among lower doses of SB203580 and proteasome inhibitors, particularly in the eotaxin-1/CCL11 production. No such prominent synergism was found on the eotaxin-3/CCL26 production. The suppression of eotaxin family production by these inhibitors may be efficacious against allergic diseases.
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PMID:Differential regulation of eotaxin-1/CCL11 and eotaxin-3/CCL26 production by the TNF-alpha and IL-4 stimulated human lung fibroblast. 1675 1

Verotoxin (VT)-producing Escherichia coli (E. coli) O157:H7 infections are frequently complicated by thrombotic angiopathy, hemolytic uremic syndrome (HUS) and neurological symptoms. The present data demonstrate that VT-1 (Shiga toxin) stimulation of macrophage-like THP-1 cells up-regulates the activity, antigen and mRNA levels of tissue factor (TF), a key cofactor of the coagulation-inflammation-thrombosis circuit. This up-regulation is accompanied by phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase), IkappaB kinase beta (IKKbeta) and extracellular signal-regulated kinase 2 (ERK2). Changes in TF mRNA levels were in parallel with the activation of NF-kappaB/Rel and Egr-1 activation, but not with AP-1. Inhibition of PI3-kinase attenuated VT-1-induced phosphorylation of IKKbeta and ERK2, and the up-regulation of TF mRNA levels. VT-1 stimulation rapidly activated c-Yes tyrosine kinase, a member of the Src family. Treatment of the cells with c-Yes antisense oligos attenuated the VT-1-induced phosphorylation of PI3-kinase, IKKbeta and ERK2, activations of NF-kappaB/Rel and Egr-1, and up-regulation of TF mRNA levels. These results suggest that VT-1-induced macrophage stimulation activates c-Yes, which then up-regulates TF expression through activation of the IKKbeta/proteasome/NF-kappaB/Rel and MEK/ERK2/Egr-1 pathways via activation of PI3-kinase. Induction of macrophage TF expression by VT-1 may play an important role in the acceleration of the coagulation-inflammation-thrombosis circuit during infections by VT-producing E. coli.
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PMID:Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: Possible signal transduction in tissue factor up-regulation. 1693 Sep 53

The respiratory tract is innervated by irritant-responsive sensory nerves, which, on stimulation, release tachykinin neuropeptides in the lung. Tachykinins modulate inflammatory responses to injury by binding to tachykinin (neurokinin) receptors present on various pulmonary cell types. In the present study, the activation of the proinflammatory transcription factor NF-kappaB in lung epithelial cells was investigated as a mechanism by which tachykinins stimulate inflammatory processes. In A549 human lung epithelial cells transfected with the tachykinin-1 receptor (Tacr1), treatment with the Tacr1 ligand substance P (SP) resulted in NF-kappaB activation, as judged by transcription of an NF-kappaB-luciferase reporter gene and production of interleukin-8, a chemokine whose expression is upregulated by NF-kappaB. SP caused a dose-dependent activation of NF-kappaB that was inhibited by the selective Tacr1 antagonist RP67580. Tacr1 is a G protein-coupled receptor capable of activating both the G(q) and G(s) families of G proteins. Expression of inhibitory peptides and constitutively active G protein mutants revealed that G(q) signaling was both necessary for Tacr1-induced NF-kappaB activation and sufficient for NF-kappaB activation in the absence of any other treatment. Treatment with pharmacological inhibitors to investigate events downstream of G(q) revealed that Tacr1-induced NF-kappaB activation proceeded through an intracellular signaling pathway that was dependent on phospholipase C, calcium, Ras, Raf-1, MEK, Erk, and proteasome function. These results identify intracellular signaling mechanisms that underlie the proinflammatory effects of tachykinins, which previously have been implicated in lung injury and disease.
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PMID:Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-kappaB via a G(q)-dependent pathway. 1704 Oct 11

The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis. In BALB/c senescent mice (approximately 2 years old), the incidence of E47-expressing pro-B cells in vivo and E47 protein steady state levels in B cell precursors in vitro were reduced. Poor expression of E47 protein was a consequence of accelerated proteasome-mediated turnover and was associated with heightened ubiquitin modification of E2A-encoded proteins in aged B cell precursors. Both MAPK and Notch activity have been previously associated with E2A-encoded protein stability in lymphocytes. Aged B cell precursors exhibited heightened levels of MAPK activity reflected in increased levels of phospho-ERK proteins. Phosphorylation of E2A-encoded proteins was also increased in aged B cell precursors and pharmacologic inhibition of MEK-1 resulted in a partial restoration of their E47 protein. Both Notch proteins and their Delta-like ligands were detected comparably in young and aged B cell precursors. Either inhibition of Notch activation via gamma-secretase or Ab blockade of Notch-Delta-like ligand interactions partially restored E47 expression in aged B cell precursors. We hypothesize that increased MAPK activity promotes phosphorylation of E2A-encoded protein in aged B cell precursors. Subsequently, E2A-encoded proteins undergo ubiquitination and accelerated degradation in a Notch-dependent process. The dysregulation of E2A-encoded protein expression may contribute to the reductions seen in early B lymphopoiesis during murine senescence.
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PMID:Accelerated Notch-dependent degradation of E47 proteins in aged B cell precursors is associated with increased ERK MAPK activation. 1733 47

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

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


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