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 cytokine interleukin-10 (IL-10) is an important regulator of immune cell function, proliferation, and survival. The IL-10 receptor (IL-10R) consists of two subunits, IL-10R1 and IL-10R2, both belonging to the class II cytokine receptor superfamily. Like other members of the cytokine receptor superfamily, IL-10R stimulation leads to activation of Jak family kinases and Stat transcription factors. To identify additional signal transduction pathways used by the IL-10R, we purified 92-kDa and 100-kDa proteins that coprecipitated with IL-10R1 from IL-10-stimulated cells. Both proteins were found to be related to the 97-kDa subunit of the regulatory component of the 26S proteasome. Subsequent studies confirmed that the IL-10R1 undergoes ligand- dependent internalization and proteasome-mediated degradation. An IL-10R1 cytoplasmic domain mutant deficient for internalization exhibited prolonged signaling through Jak1 and Stat3, reinforcing the importance of receptor internalization for signal termination.
J Interferon Cytokine Res 2006 May
PMID:Proteasome-mediated proteolysis of the interleukin-10 receptor is important for signal downregulation. 1668 56

Approximately one half of all cancer patients experience a complex metabolic status involving progressive exhaustion of adipose and skeletal muscle tissue. This condition, known as cachexia, is responsible for more than 20% of the overall deaths in cancer patients. Although its main mechanisms remain unknown, several hypotheses have been proposed. One of the pathogenic mechanisms involves leptin and hypothalamic neuropeptide-containing pathways. Orexigenic and anorexigenic neuropeptides are down-regulated respectively upregulated as a result of cancer. Other pathogenic theories consider tumour derived factors, such as LMF (Lipid Mobilising Factor) and PIF (Proteolysis-inducing Factor), to be responsible for the weight losing pattern of cancer patients via activation of various catabolic pathways (e.g. ubiquitin-proteasome proteolytic-pathway, etc.). Despite the controversial discussion of cachexia-inducing mechanisms it is clear that proinflammatory cytokines, such as TNFalpha, IFNgamma, IL-1, IL-6 and IL-8, are linked to all pathways that induce cachexia. Although only limited treatment exists for patients with cancer cachexia, recent studies with eicosapaentanoic acid showed promising effects in reversing weight losing pattern of cachectic patients. Cytokine targeted monoclonal antibodies, cytokine traps and genetic therapies are also evaluated for future therapeutic strategies.
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PMID:Clinical impact of cachexia on survival and outcome of cancer patients. 1681 78

Interferons (IFNs) stand in the frontline of defense against viral infections. In this study, we aimed at characterizing the gene expression profile specific to the antiviral effect out of the hundreds of genes involved also in other IFN activities. We found that the IFN-induced antiviral state is maintained for a prolonged time even after IFN occlusion. This was achieved through the active expression of a small set of <40 genes long after IFN was occluded, from which two groups are distinguished: one includes genes participating in direct inhibition of viral replication, such as Mx and OAS; the second group is related to antigen presentation, including all genes involved in the proteasome-to-immunoproteasome switch and class I MHC genes. Transcription of these genes continued after IFN removal and was Stat1 independent, suggesting the involvement of other signaling elements in addition to the canonical signal transduction pathway. Not less important were genes whose upregulation, in cases by many fold, is terminated once IFN is removed. Among these are viral sensing genes, such as retinoic acid-inducible gene-I protein (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and toll-like receptor (TLR), cytokines, and apoptotic-related genes. Our findings provide a systemwide depiction of prolonged intracellular antiviral protection without the need for ongoing IFN stimulation.
J Interferon Cytokine Res 2007 Aug
PMID:Upregulation of a small subset of genes drives type I interferon-induced antiviral memory. 1778 17

Many components of the class I antigen-processing pathway are thought to be regulated solely by interferon-gamma (IFN-gamma). Herein, we report type I IFN-mediated induction of proteasome activator (PA28) subunits alpha and beta, endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2, and leucine aminopeptidase (LAP). This mechanism was initiated by either synthetic RNA (poly(I-C)) or by hepatitis C virus (HCV) RNA-mediated induction of type I IFN and abrogated by blocking of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in PA28 subunit and aminopeptidase mRNA levels correlated with intrahepatic type I IFN responses and preceded intrahepatic IFN-gamma responses by several weeks. Thus, viral RNA-induced type I IFN regulates the antigen-processing machinery early during viral infection and prior to IFN-gamma response. This mechanism may contribute to the high effectiveness of type I IFN-based therapies if administered early during acute HCV infection.
J Interferon Cytokine Res 2007 Dec
PMID:Proteasome activator and antigen-processing aminopeptidases are regulated by virus-induced type I interferon in the hepatitis C virus-infected liver. 1818 38

Ubiquitin ligase enzymes promote substrate protein ubiquitination, a post-translational modification whereby the 76-amino acid protein ubiquitin is covalently bound to substrate proteins. Ubiquitination may target substrates for proteasomal degradation or regulate substrate function in a degradation-independent manner. Ubiquitination is reversible, and this is achieved by de-ubiquitinase enzymes [Jackson PK, Eldridge AG, Freed E, et al. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 2000;10(October (10)):429-39]. The first identified target of ubiquitination in the Tumor Necrosis Factor Receptor 1 (TNFR1) signaling cascade was Inhibitor of NF-kappaB (I-kappaB), which sequesters Nuclear Factors at kappa-chain promoters in B-cells (NF-kappaB) transcription factors in the cytosol. Following TNF-alpha stimulation, I-kappaB is ubiquitinated and subsequently degraded by the proteasome, permitting NF-kappaB transcriptional activity [Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002;82(April (2)):373-428]. Since this seminal finding, it is now evident that nearly every step of TNFR1 signaling is regulated by ubiquitination. In this review, we will summarize the ubiquitin/proteasome system and discuss the ubiquitin-mediated regulation of TNFR1 signaling.
Cytokine Growth Factor Rev
PMID:Ubiquitin-mediated regulation of TNFR1 signaling. 1851 72

The granulocyte colony-stimulating factor receptor (G-CSFR) is a critical regulator of granulopoiesis, but the mechanisms controlling its surface expression are poorly understood. Recent studies using transfected cell lines have suggested the activated G-CSFR is routed to the lysosome and not the proteasome. Here, we examined the role of the ubiquitin/proteasome system in regulating G-CSFR surface expression in both ts20 cells that have a temperature-sensitive E1 ubiquitin-activating enzyme and in primary human neutrophils. We show that the G-CSFR is constitutively ubiquitinated, which increases following ligand binding. In the absence of a functional E1 enzyme, ligand-induced internalization of the receptor is inhibited. Pre-treatment of ts20 transfectants with either chloroquine or MG132 inhibited ligand-induced G-CSFR degradation, suggesting a role for both lysosomes and proteasomes in regulating G-CSFR surface expression in this cell line. In neutrophils, inhibition of the proteasome but not the lysosome was found to inhibit internalization/degradation of the activated G-CSFR. Collectively, these data demonstrate the requirement for a functional ubiquitin/proteasome system in G-CSFR internalization and degradation. Our results suggest a prominent role for the proteasome in physiologic modulation of the G-CSFR, and provide further evidence for the importance of the ubiquitin/proteasome system in the initiation of negative signaling by cytokine receptors.
Cytokine 2008 Aug
PMID:Role of the proteasome in modulating native G-CSFR expression. 1855 23

Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-kappaB is a set of nuclear factors that bind to consensus DNA sequences called kappaB sites, and is essential for osteoclast formation and survival. NF-kappaB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-alpha and IL-1, which differentially regulate classical and/or alternative NF-kappaB pathways in osteoclastic cells. These pathways are also modulated by NF-kappaB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin-proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-kappaB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-kappaB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-kappaB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.
Cytokine Growth Factor Rev 2009 Feb
PMID:NF-kappaB modulators in osteolytic bone diseases. 1904 22

The mammalian reoviruses and rotaviruses have evolved specific mechanisms to evade the Type I interferon (IFN) antiviral response. Rotavirus likely represses the IFN response by at least 4 mechanisms. First, the rotavirus protein NSP1, most likely functioning as an E3 ligase, can induce proteasome-dependent degradation of the transcription factors IRF3, IRF5, and IRF7 to prevent their induction of IFN. Second, NSP1 can induce proteasome-dependent degradation of the ubiquitin ligase complex protein beta-TrCP, resulting in stabilization of I kappaB and concomitant failure of virus to activate NF-kappaB for induction of IFN. Third, rotavirus may sequester NF-kappaB in viroplasms. And fourth, rotavirus can prevent STAT1 and STAT2 nuclear translocation. The predominant mechanism for rotavirus inhibition of the IFN response is likely both rotavirus strain-specific and cell type-specific. The mammalian reoviruses also display strain-specific differences in their modulation of the IFN response. Reovirus activates RIG-I and IPS-1 for phosphorylation of IRF3. Reovirus-induced activation of MDA5 also participates in induction if IFN-beta, perhaps through activation of NF-kappaB. Reovirus likely inhibits the IFN response by at least 3 virus strain-specific mechanisms. First, the reovirus mu2 protein can induce an unusual nuclear accumulation of IRF9 and repress IFN-stimulated gene (ISG) expression, most likely by disrupting IRF9 function as part of the heterotrimeric transcription factor complex, ISGF3. Second, the reovirus sigma 3 protein can bind dsRNA and prevent activation of the latent antiviral effector protein PKR. And third, genetic approaches have identified the reovirus lambda 2 and sigma 2 proteins in virus strain-specific modulation of the IFN response, but the significance remains unclear. In sum, members of the family Reoviridae have evolved a variety of mechanisms to subvert the host's innate protective response.
J Interferon Cytokine Res 2009 Sep
PMID:Rotavirus and reovirus modulation of the interferon response. 1969 45

BMPs pattern the dorsal-ventral axis of vertebrate embryos. Smad1/5/8 transduces the BMP signal, and receives phosphorylation inputs from both MAPK and GSK3. Phosphorylation of Smad1 by MAPK and GSK3 result in its polyubiquitination and transport to the centrosome where it is degraded by the proteasome. These linker phosphorylations inhibit BMP/Smad1signaling by shortening its duration. Wnt, which negatively regulates GSK3 activity, prolongs the BMP/Smad1 signal. Remarkably, linker-phosphorylated Smad1 has been shown to be inherited asymmetrically during cell division. Drosophila contains a single Smad1/5/8 homologue, Mad, and is stabilized by phosphorylation-resistant mutations at GSK3 sites, causing Wingless-like effects. We summarize here the significance of linker-phosphorylated Smad1/Mad in relation to signal intensity and duration, and how this integrates the Wnt and BMP pathways during cell differentiation.
Cytokine Growth Factor Rev
PMID:Integration of BMP and Wnt signaling via vertebrate Smad1/5/8 and Drosophila Mad. 1989 9

Diabetic retinopathy has been considered a low-grade chronic inflammatory disease. The production of interleukin-1beta (IL-1beta) in the retina is increased, and this finding has been correlated with an increase in blood-retinal barrier permeability, suggesting that IL-1beta might have an important role in the pathogenesis of diabetic retinopathy. However, in this context, no attention has been given to interleukin-1 type I receptor (IL-1RI), which is the receptor responsible for IL-1beta triggered effects. Therefore, we investigated the effect of high glucose and IL-1beta on the IL-1RI regulation in retinal endothelial cells. A time-dependent downregulation of IL-1RI protein levels was detected in retinal endothelial cells exposed (1-24h) to high glucose, mannitol or IL-1beta. Long-term exposure (7days) to high glucose or mannitol also decreased IL-1RI protein content. IL-1RI downregulation was due to its activation by IL-1beta, since it was inhibited by the presence of anti-IL-1RI or anti-IL-1beta antibodies. Moreover, IL-1RI downregulation was prevented by lysosome inhibitors, chloroquine and ammonium chloride, but not by proteasome inhibitors, MG132 and lactacystin. We also found that IL-1RI translocates to the nucleus after high glucose or IL-1beta treatment. In conclusion, our results indicate that high glucose, probably due to osmotic stress, and IL-1beta downregulate IL-1RI in retinal endothelial cells. The downregulation of IL-1RI is triggered by its activation and is due, at least partially, to lysosomal degradation. High glucose and IL-1beta also enhance the translocation of IL-1RI to the nucleus.
Cytokine 2010 Mar
PMID:High glucose and interleukin-1beta downregulate interleukin-1 type I receptor (IL-1RI) in retinal endothelial cells by enhancing its degradation by a lysosome-dependent mechanism. 2003 11


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