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)

Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.
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PMID:Molecular targets of curcumin. 1756 14

Recently, several new classes of agents were developed to treat patients with malignant diseases. This progress has been based on the advances made in our understanding of critical pathways involved in tumor development and growth. Dysregulated processes leading to uncontrolled regulation of proliferation, cell cycle progression, angiogenesis and apoptosis have provided rational targets for novel therapies. Compounds inhibiting protein phosphorylation and signal transduction like tyrosine kinase inhibitors and inhibitors of proteasomal degradation have demonstrated promising results and were approved for the treatment of patients with malignant diseases. However, based on in vitro and in vivo studies, there is now an emerging evidence that these agents can affect the function and differentiation of normal, non-malignant cells like dendritic cells or T lymphocytes, resulting in immunosuppression. In our review we present recent data on the immune regulatory effects of tyrosine kinase inhibitors like imatinib that is approved to treat chronic myeloid leukemias, or inhibitors of FLT3, currently used to treat acute leukemias, as well as proteasome inhibitors and peroxisome proliferator-activated receptor agonists and discuss their possible role and application in the treatment of autoimmune and graft versus host disease.
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PMID:Development of novel compounds to treat autoimmune and inflammatory diseases and graft versus host reactions. 1758 49

Bim(EL) the most abundant Bim splice variant, is subject to ERK1/2-catalysed phosphorylation, which targets it for ubiquitination and proteasome-dependent destruction. In contrast, inactivation of ERK1/2, following withdrawal of survival factors, promotes stabilization of Bim(EL). It has been proposed that the RING finger protein Cbl binds to Bim(EL) and serves as its E3 ubiquitin ligase. However, this is controversial since most Cbl substrates are tyrosine phosphoproteins and yet Bim(EL) is targeted for destruction by ERK1/2-catalysed serine phosphorylation. Consequently, a role for Cbl could suggest a second pathway for Bim(EL) turnover, regulated by direct tyrosine phosphorylation, or could suggest that Bim(EL) is a coincidence detector, requiring phosphorylation by ERK1/2 and a tyrosine kinase. Here we show that degradation of Bim(EL) does not involve its tyrosine phosphorylation; indeed, Bim(EL) is not a tyrosine phosphoprotein. Furthermore, Bim(EL) fails to interact with Cbl and growth factor-stimulated, ERK1/2-dependent Bim(EL) turnover proceeds normally in Cbl-containing or Cbl-/- fibroblasts. These results indicate that Cbl is not required for ERK1/2-dependent Bim(EL) turnover in fibroblasts and epithelial cells and any role it has in other cell types is likely to be indirect.
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PMID:c-Cbl is not required for ERK1/2-dependent degradation of BimEL. 1788 40

In the present study the role of Akt/PKB (protein kinase B) in PIF- (proteolysis-inducing factor) induced protein degradation has been investigated in murine myotubes. PIF induced transient phosphorylation of Akt at Ser(473) within 30 min, which was attenuated by the PI3K (phosphoinositide 3-kinase) inhibitor LY294002 and the tyrosine kinase inhibitor genistein. Protein degradation was attenuated in myotubes expressing a dominant-negative mutant of Akt (termed DNAkt), compared with the wild-type variant, whereas it was enhanced in myotubes containing a constitutively active Akt construct (termed MyrAkt). A similar effect was observed on the induction of the ubiquitin-proteasome pathway. Phosphorylation of Akt has been linked to up-regulation of the ubiquitin-proteasome pathway through activation of NF-kappaB (nuclear factor kappaB) in a PI3K-dependent process. Protein degradation was attenuated by rapamycin, a specific inhibitor of mTOR (mammalian target of rapamycin), when added before, or up to 30 min after, addition of PIF. PIF induced transient phosphorylation of mTOR and the 70 kDa ribosomal protein S6 kinase. These results suggest that transient activation of Akt results in an increased protein degradation through activation of NF-kappaB and that this also allows for a specific synthesis of proteasome subunits.
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PMID:Involvement of phosphoinositide 3-kinase and Akt in the induction of muscle protein degradation by proteolysis-inducing factor. 1796 Nov 25

About 330 targets bind approved drugs, 270 encoded by the human genome and 60 belonging to pathogenic organisms. A large number of druggable targets have been recently proposed from preclinical and first clinical data, but a huge reservoir of putative drug targets, possibly several thousands, remains to be explored. This overview considers the different types of ligands and their selectivity in the main superfamilies of drug targets, enzymes, membrane transporters and ion channels, and the various classes of membrane and nuclear receptors with their signalling pathway. Recently approved drugs such as monoclonal antibodies, tyrosine kinase and proteasome inhibitors, and major drugs under clinical studies are reviewed with their molecular target and therapeutic interest. The druggability of emerging targets is discussed, such as multidrug resistance transporters and cystic fibrosis transmembrane conductance regulator (CFTR), hyperpolarization-activated cyclic nucleotides-gated (HCN), cyclic nucleotide-gated (CNG) and transient receptor potential (TRP) ion channels, tumour necrosis factor (TNF) and receptor activator of NFkappaB (RANK) receptors, integrins, and orphan or recently deorphanized G-protein-coupled and nuclear receptors. Large advances have been made in the therapeutical use of recombinant cytokines and growth factors (i.e. tasonermin, TNFalpha-1a; becaplermin, platelet-derived growth factor (PDGF); dibotermin-alpha, bone morphogenetic proteins (BMP)2; anakinra, interleukin-1 receptor antagonist protein (IRAP), and in enzyme replacement therapy, i.e. algasidase (alpha-galactosidase) and laronidase (alpha-l-iduronidase). New receptor classes are emerging, e.g. membrane aminopeptidases, and novel concepts are stimulating drug research, e.g. epigenetic therapy, but the molecular target of some approved drugs, such as paracetamol and imidazolines, still need to be identified.
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PMID:Drugs and their molecular targets: an updated overview. 1825 18

Rad51 protein is essential for homologous recombination repair of DNA damage, and is over-expressed in chemo- or radioresistant carcinomas. The polycyclic hydrocarbon carcinogen benzo[a]pyrene (B[a]P) affects MAPKs transduction pathways. Gefitinib (IressaR, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks growth factor-mediated cell proliferation and ERK1/2 activation. We hypothesized that gefitinib enhances B[a]P-mediated cytotoxicity by decreasing ERK1/2 activation. Exposure of human lung cancer cells to gefitinib decreased B[a]P-elicited ERK1/2 activation and induced Rad51 protein expression. Gefitinib and B[a]P co-treatment decreased Rad51 protein stability by triggering degradation via a 26S proteasome-dependent pathway. Expression of constitutive active MKK1/2 vectors (MKK1/2-CA) rescues the decreased ERK1/2 activity, and restores Rad51 protein level and stability under gefitinib and B[a]P co-treatment. Gefitinib enhances B[a]P-induced growth inhibition, cytotoxicity and mutagenicity. Co-treatment with gefitinib and B[a]P can further inhibit cell growth significantly after depletion of endogenous Rad51 by siRad51 RNA transfection. Enhancement of ERK1/2 activation by MKK1-CA expression decrease B[a]P- and gefitinib-induced cytotoxicity, and B[a]P-induced mutagenicity. Rad51 protein protects lung cancer cells from synergistic cytotoxic and mutagenic effects induced by gefitinib and B[a]P. Suppression of Rad51 protein expression may be a novel lung cancer therapeutic modality to overcome drug resistance to gefitinib.
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PMID:The role of repair protein Rad51 in synergistic cytotoxicity and mutagenicity induced by epidermal growth factor receptor inhibitor (Gefitinib, IressaR) and benzo[a]pyrene in human lung cancer. 1837 94

Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.
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PMID:Pancreatic cancer: from molecular pathogenesis to targeted therapy. 1842 34

The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.
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PMID:Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: recent advances and future perspectives. 1844 92

Our previous studies found that infectious pancreatic necrosis virus (IPNV) induces host apoptotic cell death, possibly through a newly synthesized protein trigger. Here, we examine whether IPNV infection can induce NF-kappaB activation through tyrosine kinase signalling of CHSE-214 cell death (host cell death). Using the electrophoretic mobility shift assay (EMSA) to detect transcription factor activation, we found that NF-kappaB is apparently activated 6-8 h post-IPNV infection. Using genistein (100 microg mL(-1); a tyrosine kinase inhibitor) to determine whether NF-kappaB activation requires tyrosine kinase activation, we found genistein blocks NF-kappaB activation at 8 h post-infection (p.i), and either enhances cell viability up to 50% at 12 h p.i. or blocks DNA fragmentation at 24 h p.i. Furthermore, the proteasome inhibitors PSI-I and PSI-II (both at 40 microm) also effectively blocked the NF-kappaB activation as well as stimulating a 30% increase in cell viability (30% decrease in apoptosis) at 8 and 12 h p.i. Taken together our data suggest that IPNV may induce NF-kappaB activation through tyrosine kinase signalling, which may be associated with induction of apoptosis.
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PMID:Aquatic birnavirus infection activates the transcription factor NF-kappaB via tyrosine kinase signalling leading to cell death. 1847 Nov 1

Her-2/neu (ErbB2) is a transmembrane tyrosine kinase and acts as a co-receptor for the other EGFR family members. It is well known that high expression of Her-2/neu is associated with a poor prognosis in breast cancer. Quercetin, a flavonoid present in many vegetables and fruits, has been studied extensively as a chemoprevention agent in several cancer models. In this study, we observed that quercetin decreased the level of Her-2/neu protein in time- and dose-dependent manners and also inhibited the downstream survival PI3K-Akt signaling pathway in Her-2/neu-overexpressing breast cancer SK-Br3 cells. We also observed that quercetin induced polyubiquitination of Her-2/neu. When the proteasome pathway was blocked by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies revealed that quercetin promoted interaction between Her-2/neu and Hsp90 which is a molecular chaperone involved in stabilization of Her-2/neu. In this condition, inhibition of Hsp90 activity by a specific inhibitor, geldanamycin (GA), or intracellular ATP depletion caused dissociation of Hsp90 from Her-2/neu and promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, played a crucial role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu. We believe that by using quercetin, new therapeutic strategies can be developed to treat Her-2/neu overexpressing cancers.
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PMID:Quercetin-induced ubiquitination and down-regulation of Her-2/neu. 1865 87


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