Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemic preconditioning (IP) enhances vascular endothelial growth factor (VEGF), Bcl-2 and survivin expression after myocardial infarction (MI). Mechanisms of angiogenic and anti-apoptotic effects due to IP still remain unclear. The present study attempts to address whether GSK-3beta-beta-catenin signaling in turn interacts with T-cell transcription factor/lymphoid-enhancer binding factor (TCF/LEF) and regulates these genes in the ischemic preconditioned myocardium. In a rat MI model with permanent occlusion of left anterior descending coronary artery (LAD), IP (four cycles of 4-min of ischemia and 4-min of reperfusion) significantly phosphorylated and inhibited GSK-3beta and accumulated beta-catenin in the cytosol and nucleus. Wortmannin, a PI-3 kinase inhibitor, repressed this effect in our model. We examined whether pretreatment with GSK-3beta inhibitor lithium or SB216763, mimicked IP-mediated angiogenesis and cardioprotection. Lithium- or SB216763- treated rats revealed accumulation of cytosolic and nuclear beta-catenin. This was followed by increased TCF/LEF transcriptional activity and the upregulation of VEGF, Bcl-2 and survivin mRNA expression accompanied by reduction of apoptotic cardiomyocytes and endothelial cells and increased capillary density after MI. The results of this study demonstrate, first time that inhibition of GSK-3beta followed by accumulation of beta-catenin in the cytosol and nucleus has potent anti-apoptotic and angiogenic effects after MI and that the PI3-kinase/GSK-3beta/beta-catenin signaling pathway plays an important role in IP.
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PMID:Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. 1628 8

Cyclin D3 has been shown to play a major role in the regulation of cell cycle progression in lymphocytes. It is therefore important to understand the mechanisms involved in the regulation of this protein. We have previously shown that both basal and cAMP-induced degradation of cyclin D3 in Reh cells is dependent on Thr-283 phosphorylation by glycogen synthase kinase-3beta (GSK-3beta). We now provide evidence of an alternative mechanism being involved in the regulation of cyclin D3 degradation. Treatment of lymphoid cells with okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), induces rapid phosphorylation and proteasomal degradation of cyclin D3. This degradation is not inhibited by the GSK-3beta inhibitors lithium or Kenpaullone, or by substitution of Thr-283 with Ala on cyclin D3, indicating that cyclin D3 can be degraded independently of Thr-283 phosphorylation and GSK-3beta activity. Interestingly, in vitro experiments revealed that PP1, but not PP2A, was able to dephosphorylate cyclin D3 efficiently, and PP1 was found to associate with His-tagged cyclin D3. These results support the hypothesis that PP1 constitutively keeps cyclin D3 in a stable, dephosphorylated state, and that treatment of cells with OA leads to phosphorylation and degradation of cyclin D3 through inhibition of PP1.
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PMID:Degradation of cyclin D3 independent of Thr-283 phosphorylation. 1633 Dec 57

CK2 is upregulated in rapidly dividing cells including most human tumours. Transgenic overexpression of CK2 in lymphoid or mammary lineages predisposes to transformation. Multiple signalling and oncogene pathways could be regulated by CK2 in this process. Our studies suggest that phosphorylation of critical oncogenes by CK2, as well as by other serine-threonine kinases, regulates their stability via susceptibility to the proteasomal degradation system. Beta-catenin is a transcriptional co-factor in the Wnt signalling pathway that is regulated in this fashion. Inactivating mutations in the adenomatosis polyposis coli (APC) gene, which encodes a carrier protein for beta-catenin, or stabilizing mutations in beta-catenin itself, frequently occur in human tumours. CK2 and the monomeric serine-threonine kinase GSK3 have opposing actions on beta-catenin: GSK-3 phosphorylation of the N-terminus of beta-catenin promotes degradation; while phosphorylation by CK2 in the armadillo repeat protein interaction domain protects it. Beta-catenin is overexpressed in mammary tumours occurring in mice transgenic for CK2 or a dominant negative form of GSK3, and also in mammary tumours arising following treatment with the environmental carcinogen DMBA. Experiments are underway to determine whether expression of both CK2 and kinase inactive GSK3 further accelerates tumorigenesis. Inhibitors of GSK3 under development for treatment of diabetes could promote tumours, while CK2 inhibitors should be useful agents for treatment of cancer.
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PMID:CK2 as a positive regulator of Wnt signalling and tumourigenesis. 1634 9

Progesterone pretreatment of ovariectomized rat uteri increases the number of synchronously proliferating stromal cells in response to estradiol 17-beta. To identify the signals involved in stimulating synchronous proliferation, sexually mature ovariectomized rats were injected with progesterone (2 mg) for 3 consecutive days. Estradiol 17-beta (0.2 microg) was administered to initiate cell cycle entry. Uterine samples were removed at various times after hormone administration and changes in wingless (Wnt) pathway effectors and gene targets were identified by microarray. Progesterone pretreatment decreased glycogen synthase kinase-3beta (GSK-3beta) and increased expression of T-cell factor/lymphoid enhancer factor (TCF/LEF). GSK-3beta protein decreased markedly in the uterine stroma of progesterone-pretreated uteri with the concomitant appearance of beta-catenin in these stromal cells. Translocation of beta-catenin from the cytosol to the nuclei in progesterone-pretreated stromal cells was stimulated in response to estradiol. Beta-catenin binding to TCF/LEF increased (P<0.05) in progesterone-pretreated uteri in response to estradiol. Progesterone stimulated the expression of the Wnt target gene urokinase plasminogen activator receptor (uPA-R) in the periluminal uterine stromal cells. The expression of uPA-R increased in progesterone-pretreated stromal cells in response to estradiol administration. Together, the results indicate that progesterone initiates Wnt signaling in the uterine stroma by down-regulating GSK-3beta. However, nuclear translocation of beta-catenin and sufficient complex formation with TCF/LEF to activate stromal cell cycle entry requires estradiol. Stimulation of a uterine stromal cell line to proliferate and differentiate resulted in beta-catenin accumulation, suggesting that endocrine-dependent Wnt signaling controls proliferation and differentiation (decidualization).
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PMID:Progesterone initiates Wnt-beta-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells. 1717 Feb 12

The beta-catenin signaling pathway is dysregulated in most cases of colon cancer resulting in an accumulation of nuclear beta-catenin and increased transcription of genes involved in tumor progression. This study examines the effect of retinol on beta-catenin protein levels in three all-trans retinoic acid (ATRA)-resistant human colon cancer cell lines: HCT-116, WiDr, and SW620. Each cell line was treated with increasing concentrations of retinol for 24 or 48 h. Retinol reduced beta-catenin protein levels and increased ubiquitinated beta-catenin in all cell lines. Treatment with the proteasomal inhibitor MG132 blocked the retinol-induced decrease in beta-catenin indicating retinol decreases beta-catenin by increasing proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah-1/adenomatous polyposis coli (APC), a Wnt/glycogen synthase kinase-3beta/APC, and a retinoid "X" receptor (RXR)-mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr), only the RXR-mediated pathway remains functional in each cell line. To determine if RXRs facilitate beta-catenin degradation, cells were treated with the RXR pan-antagonist, PA452, or transfected with RXRalpha small interfering RNA (siRNA). The RXR pan-antagonist and RXRalpha siRNA reduced the ability of retinol to decrease beta-catenin protein levels. Nuclear beta-catenin induces gene transcription via interaction with T cell factor/lymphoid enhancer factor (TCF/LEF) proteins. Retinol treatment decreased the transcription of a TOPFlash reporter construct and mRNA levels of the endogenous beta-catenin target genes, cyclin D1 and c-myc. These results indicate that retinol may reduce colon cancer cell growth by increasing the proteasomal degradation of beta-catenin via a mechanism potentially involving RXR.
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PMID:Retinol decreases beta-catenin protein levels in retinoic acid-resistant colon cancer cell lines. 1721 22

Wnt3a stimulates lymphoid enhancer factor/T-cell factor protein-sensitive transcription, i.e. the canonical pathway, in mouse F9 embryonal tetratocarcinoma cells expressing rat Frizzled-1. We explored the potential roles for inositol polyphosphates as mediators of Wnt signaling in the canonical path-way. Wnt3a triggers G-protein-linked phosphatidylinositol signaling, transiently generating inositol polyphosphates, especially inositol pentakisphosphate (IP(5)) accumulation. Knock-down of Galpha(q) abolishes, whereas expression of the Q209L constitutively active mutant of Galpha(q) mimics, the effects of Wnt3a on IP(5) generation and downstream signaling. Phospholipase Cbeta-1 and Cbeta-3 mediate the G protein signal to the level of phosphatidylinositol signaling. Knock-down and inhibitor studies of the enzymes responsible for generating IP(5) reveal inositol 1,4,5-trisphosphate 3-kinase and inositol polyphosphate multikinase as key mediators in the production of IP(5). Wnt3a stimulation of the canonical pathway requires accumulation of IP(5), which acts to inhibit the activity of glycogen synthase kinase-3beta, whereas stimulating casein kinase 2. Blockade of Wnt3a stimulation of IP(5) generation blocks beta-catenin accumulation, activation of lymphoid enhancer factor/T-cell factor protein-sensitive transcription, and promotion of primitive endoderm formation in response to Wnt3a. Phosphatidylinositol signaling mediates Wnt3a action in the canonical pathway, acting to generate inositol pentakisphosphate, a key second messenger of Wnt3a.
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PMID:Inositol pentakisphosphate mediates Wnt/beta-catenin signaling. 1759 65

Cholangiocarcinoma is a highly malignant neoplasm of the biliary tree. It has a high rate of mortality, and currently, there is no effective chemoprevention and treatment. This study was designed to investigate the potential effect of omega 3 polyunsaturated fatty acids (omega 3-PUFA) on human cholangiocarcinoma cell growth and to determine their mechanisms of actions. Treatment of three human cholangiocarcinoma cells (CCLP1, HuCCT1, SG231) with two omega 3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12 to 72 h resulted in a dose- and time-dependent inhibition of cell growth; in contrast, arachidonic acid, a omega 6-PUFA, had no significant effect. The omega 3-PUFA effect is due to the induction of apoptosis, given that DHA induced the cleaved form of PARP, caspase-3, and caspase-9. DHA and EPA treatment caused dephosphorylation (and hence, the activation) of glycogen synthase kinase-3beta (GSK-3beta) with a decline of beta-catenin protein. Accordingly, DHA treatment also decreased the beta-catenin-mediated T cell factor/lymphoid enhancer factor (TCF/LEF) reporter activity, and inhibited the expression of c-Met, a beta-catenin-controlled downstream gene implicated in cholangiocarcinogenesis. The GSK-3beta inhibitor, SB216763, partially prevented DHA-induced reduction of beta-catenin protein and TCF/LEF reporter activity, and restored cell growth, suggesting the involvement of GSK-3beta dephosphorylation in omega 3-PUFA-induced beta-catenin degradation. In parallel, DHA treatment also induced the formation of the beta-catenin/Axin/GSK-3beta binding complex, further leading to beta-catenin degradation. Moreover, DHA inhibited the expression of cyclooxygenase-2 (COX-2) and enhanced the expression of 15-hydroxyprostaglandin dehydrogenase, a physiologic COX-2 antagonist, in human cholangiocarcinoma cells. These findings suggest that omega 3-PUFAs block cholangiocarcinoma cell growth at least in part through inhibition of Wnt/beta-catenin and COX-2 signaling pathways. Thus, utilization of omega 3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma.
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PMID:Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. 1819 52

Beta-catenin is the central signalling molecule of the canonical Wnt pathway, where it activates target genes in a complex with lymphoid enhancer factor/T-cell factor transcription factors in the nucleus. The regulation of beta-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3beta (GSK-3beta) that phosphorylates beta-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3beta has a nuclear function in downregulating the activity of beta-catenin. Using colorectal cell lines that express a mutant form of beta-catenin, which cannot be phosphorylated by GSK-3beta and ectopically expressed mutant beta-catenin protein, we show that nuclear GSK-3beta functions in a mechanism that does not involve beta-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3beta enters the nucleus, forms a complex with beta-catenin and lowers the levels of beta-catenin/TCF-dependent transcription in a mechanism that involves GSK-3beta-Axin binding.
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PMID:Nuclear GSK-3beta inhibits the canonical Wnt signalling pathway in a beta-catenin phosphorylation-independent manner. 1822 84

Mel-18, a polycomb group (PcG) protein, has been suggested as a tumor suppressor in human breast cancer. Previously, we reported that Mel-18 has antiproliferative activity in breast cancer cells. However, its functional mechanism has not been fully elucidated. Here, we investigated the role of Mel-18 in human breast cancer. We saw an inverse correlation between Mel-18 and phospho-Akt, which were expressed at low and high levels, respectively, in primary breast tumor tissues from 40 breast cancer patients. The effect of Mel-18 on cell growth was examined in two breast cancer cell lines, SK-BR-3 and T-47D, which express relatively low and high levels of endogenous Mel-18, respectively. On Mel-18 overexpression in SK-BR-3 cells, cell growth was attenuated and G(1) arrest was observed. Likewise, suppression of Mel-18 by antisense expression in T-47D cells led to enhanced cell growth and accelerated G(1)-S phase transition. In these cells, cyclin-dependent kinase (Cdk)-4 and Cdk2 activities were affected by Mel-18, which were mediated by changes in cyclin D1 expression and p27(Kip1) phosphorylation at Thr(157), but not by INK4a/ARF genes. The changes were both dependent on the phosphatidylinositol 3-kinase/Akt signaling pathway. Akt phosphorylation at Ser(473) was reduced by Mel-18 overexpression in SK-BR-3 cells and enhanced by Mel-18 suppression in T-47D cells. Akt-mediated cytoplasmic localization of p27(Kip1) was inhibited by Mel-18 in SK-BR-3 cells. Moreover, Mel-18 overexpression showed reduced glycogen synthase kinase-3beta phosphorylation, beta-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level. Taken together, we established a linear relationship between Mel-18-->Akt-->G(1) phase regulators.
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PMID:Mel-18 negatively regulates INK4a/ARF-independent cell cycle progression via Akt inactivation in breast cancer. 1851 79

Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3beta phosphorylation at Ser9, stabilization and nuclear localization of beta-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27(Kip1) phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27(Kip1) phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.
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PMID:Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition. 1907 42


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