Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular mechanisms responsible for enhanced muscle protein breakdown in hospitalized patients, which frequently results in lean body wasting, are unknown. To determine whether the lysosomal, Ca2+-activated, and ubiquitin-proteasome proteolytic pathways are activated, we measured mRNA levels for components of these processes in muscle biopsies from severe head trauma patients. These patients exhibited negative nitrogen balance and increased rates of whole-body protein breakdown (assessed by [13C]leucine infusion) and of myofibrillar protein breakdown (assessed by 3-methylhistidine urinary excretion). Increased muscle mRNA levels for cathepsin D, m-calpain, and critical components of the ubiquitin proteolytic pathway (i.e., ubiquitin, the 14-kDa ubiquitin-conjugating enzyme E2, and proteasome subunits) paralleled these metabolic adaptations. The data clearly support a role for multiple proteolytic processes in increased muscle proteolysis. The ubiquitin proteolytic pathway could be activated by altered glucocorticoid production and/or increased circulating levels of interleukin 1beta and interleukin 6 observed in head trauma patients and account for the breakdown of myofibrillar proteins, as was recently reported in animal studies.
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PMID:Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. 861 Jan 6

Cytokine-inducible protein SSI-1 [signal transducers and activators of transcription (STAT)-induced STAT inhibitor 1, also referred to as SOCS-1 (suppressor of cytokine signaling 1) or JAB (Janus kinase-binding protein)] negatively regulates cytokine receptor signaling by inhibition of JAK kinases. The SSI family of proteins includes eight members that are structurally characterized by an SH2 domain and a C-terminal conserved region that we have called the SC-motif. In this study, we investigated the roles of these domains in the function of SSI-1. Results of reporter assays demonstrated that the pre-SH2 domain (24 aa in front of the SH2 domain) and the SH2 domain of SSI-1 were required for the suppression by SSI-1 of interleukin 6 signaling. Coexpression studies of COS7 cells revealed that these domains also were required for inhibition of three JAKs (JAK1, JAK2, and TYK2). Furthermore, deletion of the SH2 domain, but not the pre-SH2 domain, resulted in loss of association of SSI-1 with TYK2. Thus, SSI-1 associates with JAK family kinase via its SH2 domain, and the pre-SH2 domain is required for the function of SSI-1. Deletion of the SC-motif markedly reduced expression of SSI-1 protein in M1 cells, and this reduction was reversed by treatment with proteasome inhibitors, suggesting that this motif is required to protect the SSI-1 molecule from proteolytic degradation. Based on these findings, we concluded that three distinct domains of SSI-1 (the pre-SH2 domain, the SH2 domain, and the SC-motif) cooperate in the suppression of interleukin 6 signaling.
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PMID:Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling. 978 53

Cells of the M1D+ murine myeloid leukemic cell line differentiate into macrophages in response to either leukemia inhibitory factor (LIF) or interleukin 6. Previously, it was shown that LIF treatment of M1D+ cells leads to an increased expression of colony-stimulating factor (CSF) receptor mRNA encoded by c-fms. CSF-1, a macrophage growth factor, induces the survival, growth, and differentiation of mononuclear phagocytes but has not been implicated in the regulation of early myeloid cell differentiation. Here we show that low-dose LIF treatment of M1D+ cells results in CSF-1 secretion and CSF-1 receptor up-regulation. CSF-1, when applied alone, induces some M1D+ adherence and the up-regulation of lysozyme M, a macrophage-specific marker. Finally, we show that when applied together, LIF and CSF-1 act synergistically to induce macrophage morphology, phagocytosis, and the expression of the macrophage-specific markers CD11b/Mac-1 alpha chain, lysozyme M, FcgammaRII, and JE/MCP.1. These results indicate that instead of being part of exclusive pathways, as thought until this work, LIF and CSF-1 can function synergistically to further stimulate the early stages of myeloid differentiation.
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PMID:Synergistic effects of colony-stimulating factor 1 and leukemia inhibitory factor in inducing early myeloid cell differentiation. 983 Dec 45

Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (pO2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP- 1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.
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PMID:N-acetylcysteine decreases severity of acute pancreatitis in mice. 1070 32

Proinflammatory cytokines mediate the toxic effect of staphylococcal exotoxins (SE). Chlorogenic acid, a plant polyphenol, inhibited SE-induced T-cell proliferation (by 98%) and production of interleukin 1beta, tumor necrosis factor, interleukin 6, interferon gamma, monocyte chemotactic protein I (MCP-l), macrophage inflammatory protein (MIP)-lalpha, and MIP-lbeta by human peripheral blood mononuclear cells. These data indicate that chlorogenic acid may be therapeutically useful for mitigating the pathogenic effects of SE. Naturally occurring polyphenolic compounds such as chlorogenic acid may serve as a potent anti-inflammatory agent alternative to conventional chemotherapeutics.
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PMID:The polyphenol chlorogenic acid inhibits staphylococcal exotoxin-induced inflammatory cytokines and chemokines. 1202 39

Multiple myeloma (MM) remains incurable with current therapies, and novel biologically based therapies are urgently needed. Thalidomide and its analogues, as well as proteasome inhibitors, are examples of such novel agents that target both the myeloma cell and its microenvironment and can overcome classical drug resistance. In this study we demonstrate that arsenic trioxide (As2O3) mediates anti-MM activity both directly on tumor cells and indirectly by inhibiting production of myeloma growth and survival factors in the bone marrow (BM) microenvironment. Specifically, As2O3 at clinically achievable levels (2-5 microM) induces apoptosis even of drug-resistant MM cell lines and patient cells via caspase-9 activation, enhances the MM cell apoptosis induced by dexamethasone, and can overcome the antiapoptotic effects of interleukin 6. As2O3 also acts in the BM microenvironment to decrease MM cell binding to BM stromal cells, inhibits interleukin 6 and vascular endothelial growth factor secretion induced by MM cell adhesion, and blocks proliferation of MM cells adherent to BM stromal cells. These studies provide the rationale for clinical trials of As2O3, either alone or together with dexamethasone, to overcome classical drug resistance and improve outcome in patients with MM.
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PMID:Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment. 1249 18

Recent studies have shown that the transcription factor nuclear factor kappaB (NF-kappaB) regulates critical survival pathways in a variety of cancers, including human T-cell leukemia/lymphotrophic virus 1 (HTLV-1)-transformed CD4 T cells. The activation of NF-kappaB is controlled by proteasome-mediated degradation of the inhibitor of nuclear factor kappaBalpha (IkappaBalpha). We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in HTLV-1 Tax transgenic tumors in vitro and in vivo. In Tax transgenic mice, PS-341 administered thrice weekly inhibited tumor-associated NF-kappaB activity. Quantitation of proliferation, apoptosis, and interleukin 6 (IL-6) and IL-10 secretion by tumor cells in culture revealed that the effects of PS-341 on cell growth largely correlated with inhibition of pathways mediated by NF-kappaB. However, the effect of PS-341 on the growth of tumors in Tax transgenic mice revealed heterogeneity in drug responsiveness. The tumor tissues treated with PS-341 show no consistent inhibition of NFkappaB activation in vivo. Annexin V staining indicated that PS-341 response in vivo correlated with sensitivity to apoptosis induced by gamma irradiation. On the other hand, transplanted Tax tumors in Rag-1 mice showed consistent inhibition of tumor growth and prolonged survival in response to the same drug regimen. TUNEL staining indicated that PS-341 treatment sensitizes Tax tumors to DNA fragmentation.
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PMID:Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants. 1509 Apr 53

Androgen ablation and chemotherapy provide effective palliation for most patients with advanced prostate cancer, but eventually progressing androgen-independent prostate cancer threatens the lives of patients usually within a few years, mandating improvement in therapy. Proteasome inhibition has been proposed as a therapy target for the treatment of solid and hematological malignancies. The proteasome is a ubiquitous enzyme complex that is a hub for the regulation of many intracellular regulatory pathways; because of its essential function, this enzyme has become a new target for cancer treatment. Studies with bortezomib (VELCADE, formerly known as PS-341) and other proteasome inhibitors indicate that cancer cells are especially dependent on the proteasome for survival, and several mechanisms used by prostate cancer cells require proteasome function. Bortezomib has been studied extensively in vitro and in vivo, and anticancer activity has been seen in cell and animal models for several solid tumor types, including prostate cancer. A Phase I trial to determine the maximum tolerated dose of once-weekly bortezomib has been completed. This trial included a large fraction of patients with androgen-independent prostate cancer. The maximum tolerated dose was reached at 1.6 mg/m(2). A correlation was seen among bortezomib dose, proteasome inhibition, and positive modulation of serum prostate-specific antigen. There was also evidence of down-regulation of serum interleukin 6, a downstream nuclear factor kappaB effector. This Phase I trial and preclinical studies support additional testing of bortezomib in combination with radiation or chemotherapy for androgen-independent prostate cancer.
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PMID:Bortezomib as a potential treatment for prostate cancer. 1528 99

The progressive depletion of skeletal muscle is a hallmark of many types of advanced cancer and frequently is associated with debility, morbidity, and mortality. Muscle wasting is primarily mediated by the activation of the ubiquitin-proteasome system, which is responsible for degrading the bulk of intracellular proteins. E3 ubiquitin ligases control polyubiquitination, a rate-limiting step in the ubiquitin-proteasome system, but their direct involvement in muscle protein catabolism in cancer remains obscure. Here, we report the full-length cloning of E3alpha-II, a novel "N-end rule" ubiquitin ligase, and its functional involvement in cancer cachexia. E3alpha-II is highly enriched in skeletal muscle, and its expression is regulated by proinflammatory cytokines. In two different animal models of cancer cachexia, E3alpha-II was significantly induced at the onset and during the progression of muscle wasting. The E3alpha-II activation in skeletal muscle was accompanied by a sharp increase in protein ubiquitination, which could be blocked by arginine methylester, an E3alpha-selective inhibitor. Treatment of myotubes with tumor necrosis factor alpha or interleukin 6 elicited marked increases in E3alpha-II but not E3alpha-I expression and ubiquitin conjugation activity in parallel. E3alpha-II transfection markedly accelerated ubiquitin conjugation to endogenous cellular proteins in muscle cultures. These findings show that E3alpha-II plays an important role in muscle protein catabolism during cancer cachexia and suggest that E3alpha-II is a potential therapeutic target for muscle wasting.
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PMID:Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia. 1554 84

Creating conditions similar to those occurring during exposure of cells to microgravity modulates endothelial functions. We have previously demonstrated that human macrovascular endothelial cells in simulated hypogravity proliferate faster than controls, partly because they downregulate interleukin 1alpha. On the contrary, murine microvascular endothelial cells are growth inhibited in simulated hypogravity, and this is due, at least in part, to the decrease of interleukin 6. Since endothelial cells are very heterogeneous and differences between various species have been reported, we exposed human microvascular cells to gravitational unloading and found that it retards cell growth without affecting cell migration. Interestingly, we detected the induction of Tissue Inhibitor of Metalloprotease-2, which inhibits endothelial growth in vitro and angiogenesis in vivo. Together with the finding that hypogravity stimulates the synthesis of nitric oxide, involved also in neovascularization, our results underscore a modulation of the angiogenic properties of microvascular human endothelial cells. We also show that hypogravity inhibits proteasome activity, thus suggesting that post-translational mechanisms are involved in the adaptations of these cells to hypogravity. These results underscore that hypogravity differently impacts on micro- and macro-vascular human endothelial cells. In particular, these results may shed some light on the molecular mechanisms contributing to the impairment of angiogenesis observed in different models in space. Our data might also explain why bioengineered tissues to be used for regenerative medicine fail to neovascularize when assembled in simulated hypogravity.
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PMID:Gravitational unloading induces an anti-angiogenic phenotype in human microvascular endothelial cells. 1797 29


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