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 Wnt signaling pathway functions reiteratively during animal development to control cell fate decisions. Inappropriate deregulation of this pathway leads to cancer in a number of tissues. The components that transduce the Wnt signal from the cell membrane to the cell nucleus are well conserved between vertebrates and Drosophila. A pivotal Wnt effector is the protein beta-catenin/Armadillo whose stability in the cytoplasm is low in unstimulated cells. Beta-catenin/Armadillo is targetted for proteasome-mediated degradation by a protein complex to which it binds. This complex consists of Axin, a putative scaffold protein which also binds to the tumor suppressor Adenomatous polyposis coli (APC) and glycogen synthase kinase 3 (GSK3)/Shaggy. Wnt signaling somehow inhibits the kinase activity of the quaternary complex. As a consequence, beta-catenin/Armadillo accumulates in the cytoplasm, translocates to the nucleus and becomes a transcriptional co-activator of T cell factor (TCF), the ultimate nuclear target of Wnt signaling. TCF is an architectural protein, mediating the assembly of multi-protein enhancer complexes. It cooperates with other enhancer-binding proteins and, together with beta-catenin/Armadillo, stimulates the transcription of Wnt target genes. Recently, repressors have been identified that prevent TCF from being active in the absence of Wnt signaling.
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PMID:The control of beta-catenin and TCF during embryonic development and cancer. 1072 86

Previously, we reported that c-Myc is glycosylated by O-linked N-acetylglucosamine at Thr-58, a known phosphorylation site and a mutational hot spot in lymphomas. In this paper, we describe the production and characterization of two Thr-58 site-specific antibodies and use them to examine the modification of Thr-58 in living cells. One antibody specifically reacts with the Thr-58-glycosylated form of c-Myc, and the other reacts only with unmodified Thr-58 in c-Myc. Using these antibodies together with a commercial anti-Thr-58-phosphorylated c-Myc antibody, we simultaneously detected three forms of c-Myc (Thr-58-unmodified, -phosphorylated, and -glycosylated). It has been reported that Thr-58 phosphorylation is dependent on a prior phosphorylation of Ser-62. Mutagenesis of Ser-62 to Ala showed a marked decrease of Thr-58 phosphorylation and a marked increase of Thr-58 glycosylation. Growth inhibition of HL60 cells by serum starvation increases Thr-58 glycosylation and correspondingly decreases its phosphorylation. Serum stimulation has the opposite effect upon the modification status of Thr-58. A candidate kinase responsible for Thr-58 phosphorylation is the glycogen synthase kinase 3 (GSK3). Lithium, a competitive inhibitor of GSK3, decreased Thr-58 phosphorylation and increased its glycosylation. Finally, we show that the Thr-58-phosphorylated form of c-Myc predominantly accumulates in the cytoplasm rather than the nucleus upon inhibition of proteasome activity. These data suggest that hierarchical phosphorylation of Ser-62 and Thr-58 and alternative glycosylation/phosphorylation of Thr-58 together regulate the myriad functions of c-Myc in cells.
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PMID:Dynamic interplay between O-glycosylation and O-phosphorylation of nucleocytoplasmic proteins: alternative glycosylation/phosphorylation of THR-58, a known mutational hot spot of c-Myc in lymphomas, is regulated by mitogens. 1190 4

Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by beta-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and "stabilized" forms of beta-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting beta-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell-specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of beta-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on beta-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote beta-catenin degradation.
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PMID:Endostatin is a potential inhibitor of Wnt signaling. 1214 76

Resveratrol (RES), a natural phytoalexin, has antiproliferative activity in human-derived cancer cells and in rodent models of tumor development. We have previously shown that RES induced apoptotic death in estrogen-responsive MCF-7 human breast cancer cells. Recent data have indicated that the estrogen receptor-alpha (ERalpha), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, nonnuclear function of the ERalpha potentially relevant in cell proliferation and apoptosis. In our study, using MCF-7, we have analyzed the ability of RES to modulate the ERalpha-dependent PI3K pathway. Immunoprecipitation and kinase activity assays showed that RES increased the ERalpha-associated PI3K activity with a maximum stimulatory effect at concentrations close to 10 microM; concentrations >50 microM decreased PI3K activity. Stimulation of PI3K activity by RES was ERalpha-dependent since it could be blocked by the antiestrogen ICI 182,780. RES did not affect p85 protein expression but induced the proteasome-dependent degradation of the ERalpha. Nevertheless, the amount of PI3K immunoprecipitated by the ERalpha remained unchanged in presence of RES, indicating that ERalpha availability was not limiting PI3K activity. Phosphoprotein kinase B (pPKB/AKT) followed the pattern of PI3K activity, whereas RES did not affect total PKB/AKT expression. PKB/AKT downstream target glycogen synthase kinase 3 (GSK3) also showed a phosphorylation pattern that followed PI3K activity. We propose a mechanism through which RES could inhibit survival and proliferation of estrogen-responsive cells by interfering with an ERalpha-associated PI3K pathway, following a process that could be independent of the nuclear functions of the ERalpha.
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PMID:Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. 1475 Jan 65

Myc proteins regulate cell growth and division and are implicated in a wide range of human cancers. We show here that Fbw7, a component of the SCF(Fbw7) ubiquitin ligase and a tumor suppressor, promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro. Phosphorylation of c-Myc on threonine-58 (T58) by glycogen synthase kinase 3 regulates the binding of Fbw7 to c-Myc as well as Fbw7-mediated c-Myc degradation and ubiquitination. T58 is the most frequent site of c-myc mutations in lymphoma cells, and our findings suggest that c-Myc activation is one of the key oncogenic consequences of Fbw7 loss in cancer. Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis.
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PMID:The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. 1518 32

Hedgehog-regulated processing of the transcription factor cubitus interruptus (Ci) in Drosophila depends on phosphorylation of the C-terminal region of Ci by cAMP-dependent protein kinase and subsequently by casein kinase 1 and glycogen synthase kinase 3. Ci processing also requires Slimb, an F-box protein of SCF (Skp1/Cullin/F-box proteins) complex, and the proteasome, but the interplay between phosphorylation and the activity of Slimb and the proteasome remains unclear. Here we show that processing of the Gli3 protein, a homolog of Ci, also depends on phosphorylation of a set of four cAMP-dependent protein kinase sites that primes subsequent phosphorylation of adjacent casein kinase 1 and glycogen synthase kinase 3. Our gain- and loss-of-function analyses in cultured cells further reveal that betaTrCP, the vertebrate homolog of Slimb, is required for Gli3 processing, and we demonstrate that betaTrCP can bind phosphorylated Gli3 both in vitro and in vivo. We also find that the Gli3 protein is polyubiquitinated in the cell and that its processing depends on proteasome activity. Our findings provide evidence for a direct link between phosphorylation of Gli3/Ci proteins and betaTrCP/Slimb action, thus supporting the hypothesis that the processing of Gli3/Ci is affected by the proteasome.
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PMID:Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. 1637 61

The transcription factor IPF1/PDX1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of this transcription factor in beta-cells leads to diabetes, whereas reduced expression levels affect insulin expression and secretion. Therefore, it is essential to determine molecular mechanisms underlying the regulation of this key transcription factor on mRNA levels and, most importantly, on protein levels. Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. Oxidative stress, which is associated with the diabetic state, (i) increases IPF1/PDX1 Ser61 and/or Ser66 phosphorylation and (ii) increases the degradation rate and decreases the half-life of IPF-1/PDX-1 protein. In addition, we provide evidence that GSK3 activity participates in oxidative stress-induced effects on beta-cells. Thus, this current study uncovers a new mechanism that might contribute to diminished levels of IPF1/PDX1 protein and beta-cell dysfunction during the progression of diabetes.
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PMID:Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms. 1640 9

Beta-catenin is a signaling molecule that promotes cell proliferation by the induction of gene transcription through the activation of T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors. The canonical mechanism of the regulation of beta-catenin involves its phosphorylation by casein kinase 1 at the Ser-45 site and by glycogen synthase kinase 3 (GSK3) at the Thr-41, Ser-37, and Ser-33 sites. This phosphorylation targets beta-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote beta-catenin signaling through the inhibition of GSK3, resulting in reduced beta-catenin phosphorylation, its stabilization, and subsequent accumulation in the nucleus, where it stimulates TCF/LEF-dependent gene transcription. In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase A (PKA) in vitro and in intact cells at two novel sites, Ser-552 and Ser-675; (ii) phosphorylation by PKA promotes the transcriptional activity (TCF/LEF transactivation) of beta-catenin; (iii) mutation of Ser-675 attenuates the promoting effect of PKA; (iv) phosphorylation by PKA does not affect the GSK3-dependent phosphorylation of beta-catenin, its stability, or intracellular localization; and (v) phosphorylation at the Ser-675 site promotes the binding of beta-catenin to its transcriptional coactivator, CREB-binding protein. In conclusion, this study identifies a novel, noncanonical mechanism of modulation of beta-catenin signaling through direct phosphorylation of beta-catenin by PKA, promoting its interaction with CREB-binding protein.
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PMID:Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. 1647 42

Gli2 and Gli3 are the primary transcription factors that mediate Sonic hedgehog (Shh) signals in the mouse. Gli3 mainly acts as a transcriptional repressor, because the majority of full-length Gli3 protein is proteolytically processed. Gli2 is mostly regarded as a transcriptional activator, even though it is also suggested to have a weak repressing activity. What the molecular basis for its possible dual function is and how its activity is regulated by Shh signaling are largely unknown. Here we demonstrate that unlike the results seen with Gli3 and Cubitus Interruptus, the fly homolog of Gli, only a minor fraction of Gli2 is proteolytically processed to form a transcriptional repressor in vivo and that in addition to being processed, Gli2 full-length protein is readily degraded. The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. The phosphorylated Gli2 interacts directly with betaTrCP in the SCF ubiquitin-ligase complex through two binding sites, which results in Gli2 ubiquitination and subsequent degradation by the proteasome. Both processing and degradation of Gli2 are suppressed by Shh signaling in vivo. Our findings provide the first demonstration of a molecular mechanism by which the Gli2 transcriptional activity is regulated by Shh signaling.
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PMID:Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. 1661 81

Hypoxia-inducible transcription factor 1alpha (HIF-1alpha) is a key player in the response to hypoxia. Additionally, HIF-1alpha responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1alpha is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1alpha. We found that the inhibition or depletion of GSK-3 induced HIF-1alpha whereas the overexpression of GSK-3beta reduced HIF-1alpha. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1alpha. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1alpha degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1alpha to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1alpha stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.
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PMID:Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. 1732 32


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