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)

Chronic arthritis is a catabolic state associated with an inhibition of the IGF system and a decrease in body weight. Cachexia and muscular wasting is secondary to protein degradation by the ubiquitin-proteasome pathway. The aim of this work was to analyze the effect of adjuvant-induced arthritis on the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) as well as on IGF-I and IGF-binding protein-5 (IGFBP-5) gene expression in the skeletal muscle. We also studied whether the synthetic ghrelin receptor agonist, growth hormone releasing peptide-2 (GHRP-2), was able to prevent arthritis-induced changes in the skeletal muscle. Arthritis induced an increase in MuRF1, MAFbx (P < 0.01), and tumor necrosis factor (TNF)-alpha mRNA (P < 0.05) in the skeletal muscle. Arthritis decreased the serum IGF-I and its gene expression in the liver (P < 0.01), whereas it increased IGF-I and IGFBP-5 gene expression in the skeletal muscle (P < 0.01). Administration of GHRP-2 for 8 days prevented the arthritis-induced increase in muscular MuRF1, MAFbx, and TNF-alpha gene expression. GHRP-2 treatment increased the serum concentrations of IGF-I and the IGF-I mRNA in the liver and in the cardiac muscle and decreased muscular IGFBP-5 mRNA both in control and in arthritic rats (P < 0.05). GHRP-2 treatment increased muscular IGF-I mRNA in control rats (P < 0.01), but it did not modify the muscular IGF-I gene expression in arthritic rats. These data indicate that arthritis induces an increase in the activity of the ubiquitin-proteasome proteolytic pathway that is prevented by GHRP-2 administration. The parallel changes in muscular IGFBP-5 and TNF-alpha gene expression with the ubiquitin ligases suggest that they can participate in skeletal muscle alterations during chronic arthritis.
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PMID:Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle. 1603 67

Insulin receptor substrate (IRS) signaling is regulated through serine/threonine phosphorylation, with subsequent IRS degradation. This study examines the differences in IRS-1 and IRS-2 degradation in human neuroblastoma cells. SH-EP cells are glial-like, express low levels of the type I IGF-I receptor (IGF-IR) and IRS-2 and high levels of IRS-1. SH-SY5Y cells are neuroblast-like, with high levels of IGF-IR and IRS-2 but virtually no IRS-1. When stimulated with IGF-I, IRS-1 expression remains constant in SH-EP cells; however, IRS-2 in SH-SY5Y cells shows time- and concentration-dependent degradation, which requires IGF-IR activation. SH-EP cells transfected with IRS-2 and SH-SY5Y cells transfected with IRS-1 show that only IRS-2 is degraded by IGF-I treatment. When SH-EP cells are transfected with IGF-IR or suppressor of cytokine signaling, IRS-1 is degraded by IGF-I treatment. IRS-1 and -2 degradation are almost completely blocked by phosphatidylinositol 3-kinase inhibitors and partially by proteasome inhibitors. In summary, 1) IRS-2 is more sensitive to IGF-I-mediated degradation; 2) IRS degradation is mediated by phosphatidylinositol 3-kinase and proteasome sensitive pathways; and 3) high levels of IGF-IR, and possibly the subsequent increase in Akt phosphorylation, are required for efficient IRS degradation.
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PMID:Insulin-like growth factor I induces preferential degradation of insulin receptor substrate-2 through the phosphatidylinositol 3-kinase pathway in human neuroblastoma cells. 1615 Sep 16

Insulin-like growth factor binding protein-3 (IGFBP-3), the product of a tumor suppressor target gene, can modulate cell proliferation and apoptosis by IGF-I-dependent and IGF-I-independent mechanisms. IGFBP-3 controls the bioavailability of IGFs in the extracellular environment and is known to be subject to degradation by various extracellular proteases. Although nuclear localization and functions of IGFBP-3 have been described in the past, we show as the novel features of this study that the abundance of nuclear IGFBP-3 is directly regulated by ubiquitin/proteasome-dependent proteolysis. We show that IGFBP-3 degradation depends on an active ubiquitin-E1 ligase, specific 26S proteasome inhibitors can efficiently stabilize nuclear IGFBP-3, and the metabolic half-life of nuclear IGFBP-3 is strongly reduced relative to cytoplasmic IGFBP-3. Nuclear IGFBP-3 is highly polyubiquitinated at multiple lysine residues in its conserved COOH-terminal domain and stabilized through mutation of two COOH-terminal lysine residues. Moreover, we show that IGFBP-3, if ectopically expressed in the nucleus, can induce apoptotic cell death. These results suggest that ubiquitin/proteasome-mediated proteolysis of IGFBP-3 may contribute to down-regulation of apoptosis.
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PMID:Nuclear insulin-like growth factor binding protein-3 induces apoptosis and is targeted to ubiquitin/proteasome-dependent proteolysis. 1654 Jun 51

We examined the temporal relationship between portacaval anastomosis (PCA), weight gain, changes in skeletal muscle mass and molecular markers of protein synthesis, protein breakdown, and satellite cell proliferation and differentiation. Male Sprague-Dawley rats with end to side PCA (n=24) were compared with sham-operated pair-fed rats (n=24). Whole body weight, lean body mass, and forelimb grip strength were determined at weekly intervals. The skeletal muscle expression of the ubiquitin proteasome system, myostatin, its receptor (the activin 2B receptor) and its signal, cyclin-dependent kinase inhibitor (CDKI) p21, insulin-like growth factor (IGF)-I and its receptor (IGF-I receptor-alpha), and markers of satellite cell proliferation and differentiation were quantified. PCA rats did not gain body weight and had lower lean body mass, forelimb grip strength, and gastrocnemius muscle weight. The skeletal muscle expression of the mRNA of ubiquitin proteasome components was higher in PCA rats in the first 2 wk followed by a lower expression in the subsequent 2 wk (P<0.01). The mRNA and protein of myostatin, activin 2B receptor, and CDKI p21 were higher, whereas IGF-I and its receptor as well as markers of satellite cell function (proliferating nuclear cell antigen, myoD, myf5, and myogenin) were lower at weeks 3 and 4 following PCA (P < 0.05). We conclude that PCA resulted in uninhibited proteolysis in the initial 2 wk. This was followed by an adaptive response in the later 2 wk consisting of an increased expression of myostatin that may have contributed to reduced muscle protein synthesis, impaired satellite cell function, and lower skeletal muscle mass.
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PMID:Altered expression of genes regulating skeletal muscle mass in the portacaval anastomosis rat. 1718 34

The forkhead transcription factor, DAF-16, a downstream target of the insulin/IGF-I signaling pathway in C. elegans, is indispensable both for lifespan regulation and stress resistance. The molecular mechanisms involved in regulating DAF-16 transcriptional activation remain undefined. Here, we have identified an E3 ubiquitin ligase, RLE-1 (regulation of longevity by E3), which regulates aging in C. elegans. Disruption of RLE-1 expression in C. elegans increases lifespan; this extension of lifespan is due to elevated DAF-16 protein but not to changes of daf-16 mRNA levels. We have also found that RLE-1 catalyzes DAF-16 ubiquitination, leading to degradation by the proteasome. Elimination of RLE-1 expression in C. elegans causes increased transcriptional activation and sustained nuclear localization of DAF-16. Overexpression of DAF-16 in rle-1 mutants increases worm lifespan, while disruption of DAF-16 expression in rle-1 mutants reverses their longevity. Thus, RLE-1 is an E3 ubiquitin ligase of DAF-16 that regulates C. elegans aging.
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PMID:RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination. 1727 41

D-type cyclins are direct targets of extracellular signals and critical regulators of G(1) progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3beta, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3beta in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1.
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PMID:Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways. 1750 24

Glucocorticoid-induced muscle atrophy is characterized by fast-twitch or type II muscle fiber atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. Muscle proteolysis, in particular through the ubiquitin- proteasome system (UPS), is considered to play a major role in the catabolic action of glucocorticoids. The stimulation by glucocorticoids of the UPS is mediated through the increased expression of several atrogenes ('genes involved in atrophy'), such as atrogin-1 and MuRF-1, two ubiquitin ligases involved in the targeting of protein to be degraded by the proteasome machinery. Glucocorticoids also exert an anti-anabolic action by blunting muscle protein synthesis. These changes in protein turnover may result from changes in the production of two growth factors which control muscle mass, namely IGF-I and myostatin respectively anabolic and catabolic toward the skeletal muscle. The decreased production of IGF-I as well as the increased production of myostatin have been both demonstrated to contribute to the muscle atrophy caused by glucocorticoids. At the molecular level, IGF-I antagonizes the catabolic action of glucocorticoids by inhibiting, through the PI3-kinase/Akt pathway, the activity of the transcription factor FOXO, a major switch for the stimulation of several atrogenes. These recent progress in the understanding of the glucocorticoid-induced muscle atrophy should allow to define new therapies aiming to minimize this myopathy. Promising new therapeutic approaches for treating glucocorticoid-induced muscle atrophy are also presented in this review.
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PMID:Mechanisms of glucocorticoid-induced myopathy. 1837 27

Breast cancer development and progression is regulated by growth factors and steroid hormones. Although the majority of human breast cancers expresses androgen receptor (AR), the role of androgens in breast tumorigenesis remains largely unexplored. Here we demonstrate that an AR ligand, 5-alpha-dihydrotestosterone (DHT), inhibits MCF-7 breast cancer cell growth induced by insulin like growth factor 1 (IGF-I). Our results show that DHT induces association of AR with IRS-1, the major IGF-1 receptor signaling molecule. The AR/IRS-1 complex translocates to the nucleus and is recruited to gene promoters containing androgen responsive elements causing an increase of AR transcriptional activity. Moreover, IRS-1 knockdown suggests that IRS-1/AR interaction decreases the ubiquitin/proteasome dependent degradation of AR, increasing its stability. Taken together, these data indicate that nuclear IRS-1 is a novel AR regulator required to sustain AR activity and demonstrate, for the first time in breast cancer cells, the existence of a functional interplay between the IGF system and AR. This interplay may represent the molecular basis of mechanisms through which androgens exert their inhibitory role on the proliferation of breast cancer cells.
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PMID:Insulin receptor substrate 1 modulates the transcriptional activity and the stability of androgen receptor in breast cancer cells. 1852 41

Insulin receptor substrates (IRS)-1 and -2 are major substrates of insulin and type I insulin-like growth factor (IGF-I) receptor (IGF-IR) signaling. In this study, SH-EP human neuroblastoma cells are used as a model system to examine the differential roles of IRS-1 and IRS-2 on glucose-mediated apoptosis. In the presence of high glucose, IRS-1 underwent caspase-mediated degradation, followed by focal adhesion kinase (FAK) and Akt degradation and apoptosis. IRS-2 expression blocked all these changes whereas IRS-1 overexpression had no effect. In parallel, IRS-2, but not IRS-1, overexpression enhanced IGF-I-mediated Akt activation without affecting extracellular regulated kinase signaling. While IRS-1 was readily degraded by caspases, hyperglycemia-mediated IRS-2 degradation was unaffected by caspase inhibitors but blocked by proteasome and calpain inhibitors. Our data suggest that the differential degradation of IRS-1 and IRS-2 contributes to their distinct modes of action and the increased neuroprotective effects of IRS-2 in this report are due, in part, to its resistance to caspase-mediated degradation.
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PMID:Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis. 1925 21

The aim of this work was to analyse the evolution of the ubiquitin-proteasome, the myogenic regulatory factors, and the IGF-I system during the development of experimental arthritis. Arthritis was induced by adjuvant injection and rats were killed 10, 15 and 22 days later. Gastrocnemius was progressively atrophied in arthritic rats. Arthritis induced a rapid increase in muscular IGFBP-3 and IGFBP-5 and, to a lesser extent, in IGF-I mRNA. An increased expression of the muscle-specific ubiquitin ligases atrogin-1/MAFbx and MuRF-1 was observed in the gastrocnemius from day 10, reaching its maximum value on day 15. Concomitantly, the proliferation marker PCNA and the early myogenic regulatory factor MyoD were also maximally increased on day 15. Myogenin, a late-acting myogenic regulatory factor, was maximally increased on days 15 and 22. These results suggest that muscle wasting in arthritis is secondary to an increase in muscle proteolysis, rather to a decrease in muscle regeneration.
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PMID:IGF-I system, atrogenes and myogenic regulatory factors in arthritis induced muscle wasting. 1950 29


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