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)

Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). After receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate transcription of a select set of target genes. Here, we investigated the turnover of Smad3, positively regulating Smad for TGF-beta signaling. In a steady state, the inhibition of proteasome activity leads to stabilization of Smad3 protein. Smad proteins are multi-ubiquitinated and degraded independently of the phosphorylation induced by the TGF-beta receptors. Moreover, the degradation of Smad3 was enhanced by treatment with TGF-beta, and phosphorylated Smad3 was accumulated on proteasome inhibition. Ubiquitination of phosphorylated Smad3 but not Smad3(3SA), a receptor-mediated phosphorylation-incompetent mutant, was observed in the nucleus after treatment with TGF-beta. These findings suggest that, in a steady state, Smad3 is constitutively degraded via the ubiquitin-proteasome pathway in the cytoplasm and that, in response to TGF-beta, it is phosphorylated and translocated into the nucleus, where it is degraded through the ubiquitin-proteasome pathway.
J Interferon Cytokine Res 2004 Jan
PMID:Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-beta signaling. 1498 84

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins related to signal transduction. Cytokine and growth factor-dependent aberrant proliferation has been implicated in renal cell carcinoma (RCC). We hypothesized that inhibiting the proteasome function might activate a proapoptotic signal transduction by modulating the cytokine and growth factor related signal transduction pathway. We therefore investigated the effectiveness of a proteasome inhibitor in the treatment of RCC regarding the involvement of Mitogen-activated protein kinases (MAP kinases), because MAP kinases are major signal transduction molecules that are known to play a pivotal role in cancer cell proliferation or apoptosis triggered by extra-cellular cytokines and growth factors. A proteasome inhibitor, MG132 inhibited the proliferation of RCC cell lines, 786-O and KU20-01 in a time and dose-dependent manner. 786-O cells have truncated von-Hippel Lindau (VHL) tumor suppressor gene protein due to a one base pair deletion at exon 1, whereas KU20-01 cells have a wild-type VHL protein. MG132 induced apoptosis in both cell lines. The inhibition of the ubiquitin-proteasome pathways was confirmed by the accumulation of ubiquitin-tagged proteins. MG132 induced the phosphorylation of ERK at 4 h and thereafter persisted for 8 to 16 h. In contrast, JNK and p38 activation persisted for longer periods and remained enhanced until 24 h. The concomitant activation of effector caspases, caspase-3 and caspase-7 was observed in 786-O cells. The inhibition of the proteasome function can induce apoptosis in RCC irrespective of the VHL protein status. The persistence of JNK and p38 activation may therefore be a unique mechanism underlying MG132 induced apoptosis.
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PMID:Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. 1528 72

Neuronal injury triggers the release of ciliary neurotrophic factor (CNTF), promoting local neuronal repair but producing systemic effects of anorexia and lean body weight loss. Due to the rapid rate of systemic protein loss stimulated by CNTF, we hypothesized involvement of the hepatic ubiquitin-proteasome proteolytic (UPP) pathway in CNTF-induced proteolysis. To assess the role of central CNTF in systemic UPP regulation, we measured hepatic UPP mRNA and proteasome activity in a rat model of neuronal injury and determined alterations induced by intracerebroventricular (ICV) administration of CNTF-neutralizing antibody or additional exogenous CNTF. We also assessed proteolytic parameters and nutritional status by measuring caloric intake, body weight, and protein levels. We produced neuronal injury by implanting a lateral ventricle cannula and giving daily ICV saline bolus injections, which increased hepatic 20S proteasome mRNA and enzymatic activity while reducing caloric intake, body weight, and protein levels compared to controls. Administration of ICV anti-CNTF antibodies (but not control antibodies) prevented these effects. Addition of exogenous CNTF augmented the weight loss along with the increases in 20S proteasome mRNA and proteolytic activity induced by neuronal injury. We conclude that CNTF decreases lean body weight through a combination of appetite inhibition and UPP pathway activation.
Cytokine 2004 Sep 21
PMID:Ciliary neurotrophic factor upregulates ubiquitin-proteasome components in a rat model of neuronal injury. 1530 43

The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with age-matched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), macrophage chemoattractant protein-5 (MCP-5), soluble tumor necrosis factor receptor-1 (sTNFR1), IL-12p70, tumor necrosis factor-alpha (TNF-alpha), and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro, and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison with controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts.
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PMID:The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells. 1570 19

Nuclear factor (NF)-kappaB is an important regulator of inflammatory gene expression. Transcriptional regulation of Nos2, the inducible nitric-oxide synthase (iNOS) gene, is complex and not fully understood, but appears to be regulated in part by NF-kappaB. To further understand the role of NF-kappaB in Nos2 expression, we compared three functionally distinct NF-kappaB inhibitors on NF-kappaB transactivation and iNOS induction by rat C6 glial cells. Cytokine-induced activation of a consensus NF-kappaB-reporter gene was concentration-dependently inhibited by BAY 11-7082, MG-132, and helenalin. The rank order of potency was MG-132>helenalin>BAY 11-7082, with low concentrations of helenalin stimulating reporter gene activity. Cytokine-stimulated iNOS expression, measured by nitrite accumulation and in vitro l-citrulline production, was similarly reduced by exposing C6 cells to the NF-kappaB inhibitors. Surprisingly, activation of Nos2-reporter gene constructs containing the proximal 188 bp (containing one kappaB site) or proximal 94 bp (no kappaB site) of the rat promoter also was inhibited with the same rank order of potency. Interestingly, low concentrations of helenalin increased activity of both promoter constructs, while BAY 11-7082 poorly inhibited the 94-bp activity. This is the first report describing BAY 11-7082 and helenalin effects on iNOS expression in astroglia. Given the reported mechanism of actions for these inhibitors, cytokine-induced glial iNOS expression appears more sensitive to disruption of proteasome degradation and p65 function than modulation of IkappaB phosphorylation. These findings may foster the design of therapeutic agents aimed at NF-kappaB-associated pathways involved in neuroinflammation, especially iNOS expression.
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PMID:Effects of mechanistically distinct NF-kappaB inhibitors on glial inducible nitric-oxide synthase expression. 1589 May 51

Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional complex that has been recognized primarily for its role in the maintenance of oxygen and energy homoeostasis. The HIF-1alpha subunit is O(2) labile and is degraded by the proteasome following prolyl-hydroxylation and ubiquitination in normoxic cells. The present review summarizes evidence that HIF-1 is also involved in immune reactions. Immunomodulatory peptides, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), stimulate HIF-1 dependent gene expression even in normoxic cells. Both the hypoxic and the cytokine-induced activation of HIF-1 involve the phosphatidylinositol- 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling pathways. In addition, heat shock proteins (HSP) and other cofactors interact with HIF-1 subunits. HIF-1 increases the transcription of several genes for proteins that promote blood flow and inflammation, including vascular endothelial growth factor (VEGF), heme oxygenase-1, endothelial and inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2). The pharmacologic activation of the HIF-1 complex can be desirable in ischemic and inflammatory disorders. In contrast, HIF-1 blockade may be beneficial to prevent tumor angiogenesis and tumor growth.
J Interferon Cytokine Res 2005 Jun
PMID:Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. 1595 53

Interferon (IFN) regulatory factor-1 (IRF-1) deregulation in ras-transformed mouse fibroblasts (RS485) was studied. Treatment with the proteasome inhibitor MG132 did not alter the constitutive IRF-1 protein levels in RS485 but significantly increased them in nontransformed NIH 3T3 cells at 4 h after serum stimulation of synchronized cultures. Because IRF-1 protein levels in NIH 3T3 are minimal at 4 h after serum starvation, the cyclic expression of IRF-1 in NIH 3T3 appears to be partially due to proteasome activity; however, proteasome activity in RS485 did not appear to be defective. In NIH 3T3 and RS485 cells treated with cycloheximide, there were similar rapid drops in IRF-1 protein levels, and the addition of MG132 along with cycloheximide prevented protein loss in both cell lines. Northern blot analyses of synchronized cultures showed that the IRF-1 message closely mirrored the protein expression pattern in both NIH 3T3 and RS485 cells. In synchronized cells treated with the transcription inhibitor actinomycin D, IRF-1 mRNA half-life was only marginally longer in ras-transformed fibroblasts than in the nontransformed cells, and this difference would contribute minimally to protein overexpression. These findings indicate that IRF-1 deregulation in RS485 cells occurs primarily at the transcriptional level.
J Interferon Cytokine Res 2005 Jul
PMID:Mechanisms of deregulation of IFN regulatory factor-1 in ras-transformed fibroblasts. 1602 87

Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)- and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.
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PMID:SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. 1619 87

Changes in circulating cytokines might serve as predictors of compound-evoked inflammatory responses. CD-1 mice were treated with lipopolysaccharide (LPS; 0.2 ml of 0.25 mg/ml, intraperitoneal) for subsequent expression measurement of plasma cytokine protein expression at 24-h post-treatment using multiple antibody Western blot, and at both 2-h and 24-h post-treatment using antibody array and suspension bead array. Antibody array provided a semi-qualitative assessment and suggested significantly increased expression of GCSF at 2-h post-treatment and GCSF, IL-6, IL-12, MCP-1, MCP-5, RANTES and sTNFR1 at 24-h post-treatment. Densitometric analysis of multiple antibody Western blots provided a semi-quantitative assessment and indicated significantly increased expression of IL-6, IL-12, IL-17, GCSF, eotaxin, and MCP-2 at 24-h post-treatment. The suspension bead array yielded statistically significant cytokine protein expression increases for IL-6, IL-10, IFNgamma and TNFalpha at both 2-h and 24-h post-treatments, while significant expression at 24-h post-treatment only was noted for IL-1beta, IL-5, IL-12 and GM-CSF. Suspension bead array provided the greatest range of detection, revealing subtle increased expression of GM-CSF, IL-1beta, IL-5, IL-10, TNFalpha and IFNgamma at 24-h post-treatment, not detected by antibody array or multiple antibody Western blot. Suspension bead array proved to be the best method for detection of LPS-evoked changes in plasma cytokine levels.
Cytokine 2005 Dec 07
PMID:Comparative methods for multiplex analysis of cytokine protein expression in plasma of lipopolysaccharide-treated mice. 1625 31

Cytokines, hormones or growth factors induce a variety of biological responses including proliferation, differentiation and apoptosis. After binding to their specific cell surface receptors, these stimuli induce the activation of a number of signaling pathways including the activation of JAK (JAnus Kinase) proteins by auto and transphosphorylation. Activated JAK phosphorylate the receptor chains on tyrosines, creating docking sites for cytoplasmic transcription factors named STAT (Signal Transducers and Activators of Transcription). Furthermore, the JAK phosphorylate the STAT which form dimers and migrate to the nucleus where they bind to specific DNA sequences leading to the activation of transcription. The multiplicity of JAK (4 members) and STAT (7 members) and their associations with multiple possible partners allow the formation of various STAT homo and heterodimers and STAT-containing transcriptional complexes. Each of these complexes lead to the specific regulation of gene transcription. Negative regulation of the JAK/STAT signaling pathway is crucial to switch off the cytokine/growth factors' signal. Three families of proteins : the phosphotyrosine phosphatases (SHPs, CD45, PTP1B/TC-PTP), the SOCS proteins (Suppressors Of Cytokine Signaling) and the PIAS (Protein Inhibitor of Activated STAT) are involved in this process. These proteins act at various levels of the JAK/STAT pathway. Thus, tyrosine-phosphatases dephosphorylate activated JAK, STAT or cytokine receptors. PIAS interact with activated STAT and inhibit their DNA binding or their transactivating capacity, probably in relation with their intrinsic SUMO E3-ligase activity. The tyrosine phosphatases and the PIAS are constitutively present in the cell and represent a first level of regulation. The SOCS, which represent a second level of JAK/STAT negative control, are induced by cytokines and exert a negative feed-back loop. Indeed, they interact with activated JAK or with phosphorylated receptors, inhibiting the recruitment of STAT, the activation of the JAK enzymatic activity, or inducing the proteasome-dependant degradation of activated JAK or receptors.
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PMID:[Negative regulation of the JAK/STAT: pathway implication in tumorigenesis]. 1626 68


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