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)

The broad range of biological responses elicited by transforming growth factor-beta (TGF-beta) in various types of tissues and cells is mainly determined by the expression level and activity of the effector proteins Smad2 and Smad3. It is not fully understood how the baseline properties of Smad3 are regulated, although this molecule is in complex with many other proteins at the steady state. Here we show that nonactivated Smad3, but not Smad2, undergoes proteasome-dependent degradation due to the concerted action of the scaffolding protein Axin and its associated kinase, glycogen synthase kinase 3-beta (GSK3-beta). Smad3 physically interacts with Axin and GSK3-beta only in the absence of TGF-beta. Reduction in the expression or activity of Axin/GSK3-beta leads to increased Smad3 stability and transcriptional activity without affecting TGF-beta receptors or Smad2, whereas overexpression of these proteins promotes Smad3 basal degradation and desensitizes cells to TGF-beta. Mechanistically, Axin facilitates GSK3-beta-mediated phosphorylation of Smad3 at Thr66, which triggers Smad3 ubiquitination and degradation. Thr66 mutants of Smad3 show altered protein stability and hence transcriptional activity. These results indicate that the steady-state stability of Smad3 is an important determinant of cellular sensitivity to TGF-beta, and suggest a new function of the Axin/GSK3-beta complex in modulating critical TGF-beta/Smad3-regulated processes during development and tumor progression.
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PMID:Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. 1817 67

Cancer cachexia is a debilitating and life-threatening syndrome that accounts for at least 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. The loss of lean body mass is the main characteristic of cancer cachexia and the principal cause of function impairment, fatigue and respiratory complications. It is the result of an imbalance between protein synthesis and protein degradation, the mechanisms underlying such alteration being multiple and partially known. Current therapy of cancer cachexia continues to be extremely poor. However, in the last decade, the attention has focused just on the skeletal muscle, as a potential target of therapy, with the aim to discover drugs capable to inhibit the catabolic processes and to stimulate the anabolic pathways. The skeletal muscle has been faced at different levels such as the mediators (cytokines and tumor-derived factors), the receptors (TNF-alpha and androgen receptors), the proteolytic pathways (calpains and ubiquitin-proteasome), the intracellullar signalling pathways (NF-kB, AP-1, FOXO, PKR), and the negative modulators of muscle growth/hypertrophy (myostatin, GSK3-beta). Most of the drugs that have been tested have shown to be effective, at least in experimental models of cancer cachexia. It remains to define their safety, tolerance and efficacy in humans through large, adequate, clinical trials. However, the impression is that there is a light at the back of the tunnel.
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PMID:Skeletal muscle in cancer cachexia: the ideal target of drug therapy. 1853 52

The transcriptional coactivator AIB1 is an oncogene overexpressed in different types of tumors, including breast cancer. Although the subcellular compartimentalization of AIB1 seems to be intimately linked to abnormal proliferation, the molecular mechanisms that regulate its subcellular distribution are not well defined. Here, we report that the nuclear accumulation and half-life of AIB1 vary between cancer cell lines. Using these differences as an experimental model, our results reveal that alterations to the Akt signaling pathway and nuclear export determine the stability of AIB1 and nuclear content of this coactivator. Moreover, our results show that AIB1 is degraded in the nucleus by the proteasome in an ubiquitin-dependent manner. However, this process does not require phosphorylation by GSK3, thereby revealing an alternative mechanism for regulating the turnover of AIB1. We define a new region at the carboxy terminus of AIB1 that is required for proteasome-dependent transcriptional activation and is preceded by a PEST domain that is required for adequate protein turnover. Based on differences in Akt signaling and the subcellular distribution of AIB1 between different cell lines, our results suggest that dysregulation of nuclear shuttling and proteasomal degradation may modulate the oncogenic potential of AIB1.
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PMID:Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation. 1859 48

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5+ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of anti-apoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n=44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCdelta and a proteasome-dependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCdelta downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies.
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PMID:The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. 1958 35

The multi-protein beta-catenin destruction complex tightly regulates beta-catenin protein levels by shuttling beta-catenin to the proteasome. Glycogen synthase kinase 3beta (GSK3beta), a key serine/threonine kinase in the destruction complex, is responsible for several phosphorylation events that mark beta-catenin for ubiquitination and subsequent degradation. Because modulation of both beta-catenin and GSK3beta activity may have important implications for treating disease, a complete understanding of the mechanisms that regulate the beta-catenin/GSK3beta interaction is warranted. We screened an arrayed lentivirus library expressing small hairpin RNAs (shRNAs) targeting 5,201 human druggable genes for silencing events that activate a beta-catenin pathway reporter (BAR) in synergy with 6-bromoindirubin-3'oxime (BIO), a specific inhibitor of GSK3beta. Top screen hits included shRNAs targeting dihydrofolate reductase (DHFR), the target of the anti-inflammatory compound methotrexate. Exposure of cells to BIO plus methotrexate resulted in potent synergistic activation of BAR activity, reduction of beta-catenin phosphorylation at GSK3-specific sites, and accumulation of nuclear beta-catenin. Furthermore, the observed synergy correlated with inhibitory phosphorylation of GSK3beta and was neutralized upon inhibition of phosphatidyl inositol 3-kinase (PI3K). Linking these observations to inflammation, we also observed synergistic inhibition of lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines (TNFalpha, IL-6, and IL-12), and increased production of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells exposed to GSK3 inhibitors and methotrexate. Our data establish DHFR as a novel modulator of beta-catenin and GSK3 signaling and raise several implications for clinical use of combined methotrexate and GSK3 inhibitors as treatment for inflammatory disease.
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PMID:A lentivirus-mediated genetic screen identifies dihydrofolate reductase (DHFR) as a modulator of beta-catenin/GSK3 signaling. 1972 91

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.
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PMID:Integration of BMP and Wnt signaling via vertebrate Smad1/5/8 and Drosophila Mad. 1989 9

High glucose (HG) has been shown to induce insulin resistance in both type 1 and type 2 diabetes. However, the molecular mechanism behind this phenomenon is unknown. Insulin receptor substrate (IRS) proteins are the key signaling molecules that mediate insulin's intracellular actions. Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. Overexpression of IRS1 with mutation of serine(332) to alanine partially prevents HG-induced IRS1 degradation. Furthermore, overexpression of constitutively active GSK3 beta was sufficient to induce IRS1 degradation. Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1.
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PMID:Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. 2046 47

Adenomatous polyposis coli (APC), a tumor suppressor commonly mutated in cancer, is a cytoskeletal organizer for cell migration and a scaffold for GSK3 beta/CKI-mediated phosphorylation and degradation of the Wnt effector beta-catenin. It remains unclear whether these different APC functions are coupled, or independently regulated and localized. In primary endothelial cells, we show that GSK3 beta/CKI-phosphorylated APC localizes to microtubule-dependent clusters at the tips of membrane extensions. Loss of GSK3 beta/CKI-phosphorylated APC from these clusters correlates with a decrease in cell migration. GSK3 beta/CKI-phosphorylated APC and beta-catenin at clusters is degraded rapidly by the proteasome, but inhibition of GSK3 beta/CKI does not increase beta-catenin-mediated transcription. GSK3 beta/CKI-phosphorylated and -nonphosphorylated APC also localize along adherens junctions, which requires actin and cell-cell adhesion. Significantly, inhibition of cell-cell adhesion results in loss of lateral membrane APC and a concomitant increase in GSK3 beta/CKI-phosphorylated APC in clusters. These results uncouple different APC functions and show that GSK3 beta/CKI phosphorylation regulates APC clusters and cell migration independently of cell-cell adhesion and beta-catenin transcriptional activity.
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PMID:Adenomatous polyposis coli regulates endothelial cell migration independent of roles in beta-catenin signaling and cell-cell adhesion. 2051 33

2-deoxy-D-glucose (2DG) is known as a synthetic inhibitor of glucose. 2DG regulates various cellular responses including proliferation, apoptosis and differentiation by regulation of glucose metabolism in cancer cells. However, the effects of 2DG in normal cells, including chondrocytes, are not clear yet. We examined the effects of 2DG on dedifferentiation with a focus on the beta-catenin pathway in rabbit articular chondrocytes. The rabbit articular chondrocytes were treated with 5 mM 2DG for the indicated time periods or with various concentrations of 2DG for 24 h, and the expression of type II collagen, c-jun and beta-catenin was determined by Western blot, RT-PCR, immunofluorescence staining and immunohistochemical staining and reduction of sulfated proteoglycan synthesis detected by Alcain blue staining. Luciferase assay using a TCF (T cell factor)/LEF (lymphoid enhancer factor) reporter construct was used to demonstrate the transcriptional activity of beta-catenin. We found that 2DG treatment caused a decrease of type II collagen expression. 2DG induced dedifferentiation was dependent on activation of beta-catenin, as the 2DG stimulated accumulation of beta-catenin, which is characterized by translocation of beta-catenin into the nucleus determined by immunofluorescence staining and luciferase assay. Inhibition of beta-catenin degradation by inhibition of glycogen synthase kinase 3-beta with lithium chloride (LiCl) or inhibition of proteasome with z-Leu-Leu-Leu-CHO (MG132) accelerated the decrease of type II collagen expression in the chondrocytes. 2DG regulated the post-translational level of beta-catenin whereas the transcriptional level of beta-catenin was not altered. These results collectively showed that 2DG regulates dedifferentiation via beta-catenin pathway in rabbit articular chondrocytes.
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PMID:2-Deoxy-D-glucose regulates dedifferentiation through beta-catenin pathway in rabbit articular chondrocytes. 2053 Sep 83

The nuclear and oncogenic BCL-3 protein activates or represses gene transcription when bound to NF-kappaB proteins p50 and p52, yet the molecules that specifically interact with BCL-3 and drive BCL-3-mediated effects on gene expression remain largely uncharacterized. Moreover, GSK3-mediated phosphorylation of BCL-3 triggers its degradation through the proteasome, but the proteins involved in this degradative pathway are poorly characterized. Biochemical purification of interacting partners of BCL-3 led to the identification of CtBP as a molecule required for the ability of BCL-3 to repress gene transcription. CtBP is also required for the oncogenic potential of BCL-3 and for its ability to inhibit UV-mediated cell apoptosis in keratinocytes. We also defined the E3 ligase TBLR1 as a protein involved in BCL-3 degradation through a GSK3-independent pathway. Thus, our data demonstrate that the LSD1/CtBP complex is required for the repressing abilities of an oncogenic I kappaB protein, and they establish a functional link between the E3 ligase TBLR1 and NF-kappaB.
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PMID:The repressing function of the oncoprotein BCL-3 requires CtBP, while its polyubiquitination and degradation involve the E3 ligase TBLR1. 2054 59


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