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:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Occupational exposure to asphalt fumes may pose a health risk. Experimental studies using animal and in vitro models indicate that condensates from asphalt fumes are genotoxic and can promote skin tumorigenesis. Enhanced activity of activator protein-1 (AP-1) is frequently associated with the promotion of skin tumorigenesis. The current study investigated the effect of exposure to asphalt fumes on AP-1 activation in mouse JB6 P+ epidermal cells and the skin of transgenic mice expressing the AP-1 luciferase reporter gene. Asphalt fumes were generated from a dynamic generation system that simulated road-paving conditions. Exposure to asphalt fumes significantly increased AP-1 activity in JB6 P+ cells as well as in cultured keratinocytes isolated from transgenic mice expressing AP-1 reporter. In addition, topical application of asphalt fumes by painting the tail skin of mice increased AP-1 activity by 14-fold. Exposure to asphalt fumes promoted basal as well as epidermal growth factor-stimulated anchorage-independent growth of JB6 P+ cells in soft agar. It activated phosphatidylinositol 3-kinase and induced phosphorylation of Akt at Ser-473/Thr-308, and concurrently activated downstream p70 S6 kinase as well as glycogen synthase kinase-3beta. Asphalt fumes transiently activated c-Jun NH2-terminal kinases without affecting extracellular signal-regulated kinases and p38 mitogen-activated protein kinases. Further study indicated that blockage of phosphatidylinositol 3-kinase activation eliminated asphalt fume-stimulated AP-1 activation and formation of anchorage-independent colonies in soft agar. This is the first report showing that exposure to asphalt fumes can activate AP-1 and intracellular signaling that may promote skin tumorigenesis, thus providing important evidence on the potential involvement of exposure to asphalt fumes in skin carcinogenesis.
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PMID:Exposure to asphalt fumes activates activator protein-1 through the phosphatidylinositol 3-kinase/Akt signaling pathway in mouse epidermal cells. 1294

The c-Myc protein is a transcription factor that is a central regulator of cell growth and proliferation. Thr-58 is a major phosphorylation site in c-Myc and is a mutational hotspot in Burkitt's and other aggressive human lymphomas, indicating that Thr-58 phosphorylation restricts the oncogenic potential of c-Myc. Mutation of Thr-58 is also associated with increased c-Myc protein stability. Here we show that inhibition of glycogen synthase kinase-3 (GSK-3) activity with lithium increases c-Myc stability and inhibits phosphorylation of c-Myc specifically at Thr-58 in vivo. Conversely, overexpression of GSK-3 alpha or GSK-3 beta enhances Thr-58 phosphorylation and ubiquitination of c-Myc. Together, these observations suggest that phosphorylation of Thr-58 mediated by GSK-3 facilitates c-Myc rapid proteolysis by the ubiquitin pathway. Furthermore, we demonstrate that GSK-3 binds c-Myc in vivo and in vitro and that GSK-3 colocalizes with c-Myc in the nucleus, strongly arguing that GSK-3 is the c-Myc Thr-58 kinase. We found that c-MycS, which lacks the N-terminal 100 amino acids of c-Myc, is unable to bind GSK-3; however, mutation of Ser-62, the priming phosphorylation site necessary for Thr-58 phosphorylation, does not disrupt GSK-3 binding. Finally, we show that Thr-58 phosphorylation alters the subnuclear localization of c-Myc, enhancing its localization to discrete nuclear bodies together with GSK-3.
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PMID:Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. 1456 37

Inhibitor-2 (I2) is a thermostable protein that specifically binds to the catalytic subunit of protein phosphatase-1 (PP1), resulting in the formation of the inactive holoenzyme, ATP-Mg-dependent phosphatase. Phosphorylation of I2 at Thr-72 by glycogen synthase kinase-3 (GSK-3) results in activation of the phosphatase, suggesting that kinase action triggers conformational change in the complex. In this paper, we characterize the effect of GSK-3 phosphorylation on the structure of free state I2[1-172] by nuclear magnetic resonance and circular dichroism spectroscopy, and show that phosphorylation has no significant effect on its conformation. We conclude that the conformational changes of ATP-Mg-dependent phosphatase induced by GSK-3 phosphorylation must depend on the interactions between PP1 and I2.
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PMID:Phosphorylation by glycogen synthase kinase of inhibitor-2 does not change its structure in free state. 1462 75

With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition data of 52 paullone entities, which were aligned by a docking routine into the ATP-binding cleft of a CDK1/cyclin B homology model. Variation of grid spacing and column filtering were used during the optimization of the models. The predictive ability of the models was shown by a leave-one-out cross-validation and the prediction of an independent set of test compounds, which were synthesized especially for this purpose. Besides paullones with the basic indolo[3,2-d][1]benzazepine core, the test set comprised novel thieno[3',2':2,3]azepino[4,5-b]indoles, pyrido[2',3':2,3]azepino[4,5-b]indoles, and a pyrido[3',2':4,5]pyrrolo[3,2-d][1]benzazepine. The best statistical values for the CoMSIA were obtained for the CDK1-models (r(2)() = 0.929 and q(2)() = 0.699), which were clearly superior to the models for CDK5 (r(2)() = 0.874 and q(2)() = 0.652) and GSK-3 (r(2)() = 0.871 and q(2)() = 0.554).
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PMID:Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones. 1469 17

The CDC25 phosphatases regulate the cell division cycle by controlling the activity of cyclin-dependent kinases. While screening for inhibitors of phosphatases among natural products we repeatedly found that some polyprenyl-hydroquinones and polyprenyl-furans (furanoterpenoids) (furospongins, furospinosulins) were potent CDC25 phosphatase inhibitors. These compounds were extracted, isolated and identified independently from three sponge species (Spongia officinalis, Ircinia spinulosa, Ircinia muscarum), collected at different locations in the Mediterranean Sea. The compounds were inactive on the Ser/Thr phosphatase PP2C-alpha and on three kinases (CDK1, CDK5, GSK-3), suggesting that some potent and selective CDC25 phosphatase might be designed from these initial structures.
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PMID:Polyprenyl-hydroquinones and -furans from three marine sponges inhibit the cell cycle regulating phosphatase CDC25A. 1497 10

Human tau-protein kinase I (TPK I; also known as glycogen synthase kinase 3 beta; GSK3 beta) is a serine/threonine protein kinase that participates in Alzheimer's disease. Here, binary complex structures of full-length TPK I/GSK3 beta with the ATP analogues ADP and AMPPNP solved by the X-ray diffraction method at 2.1 and 1.8 A resolution, respectively, are reported. TPK I/GSK3 beta is composed of three domains: an N-terminal domain consisting of a closed beta-barrel structure, a C-terminal domain containing a 'kinase fold' structure and a small extra-domain subsequent to the C-terminal domain. The catalytic site is between the two major domains and has an ATP-analogue molecule in its ATP-binding site. The adenine ring is buried in the hydrophobic pocket and interacts specifically with the main-chain atoms of the hinge loop. The overall structure and substrate-binding residues are similar to those observed in other Ser/Thr protein kinases, while Arg141 (which is not conserved among other Ser/Thr protein kinases) is one of the key residues for specific ATP/ADP recognition by TPK I/GSK3 beta. No residues are phosphorylated, while the orientation of the activation loop in TPK I/GSK3 beta is similar to that in phosphorylated CDK2 and ERK2, suggesting that TPK I/GSK3 beta falls into a conformation that enables it to be constitutively active.
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PMID:Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta. 1499 67

Beta-Catenin, a member of the Wnt signaling pathway, is downregulated by glycogen synthase kinase-3beta (GSK-3beta)-dependent phosphorylation of Ser/Thr residues in the N-terminus of the protein, followed by ubiquitination and proteosomal degradation. In human and rodent cancers, mutations that substitute one of the critical Ser/Thr residues in the GSK-3beta region of beta-catenin stabilize the protein and activate beta-catenin/TCF/LEF target genes. This study examined three oncogenic beta-catenin mutants from rat colon tumors containing substitutions adjacent to amino-acid residue Ser33, a key target for phosphorylation by GSK-3beta. Compared with wild-type beta-catenin (WT), the beta-catenin mutants D32G, D32N, and D32Y strongly activated TCF-4-dependent transcription in HEK293 cells, and there was accumulation of beta-catenin in the cell lysates. Immunoblotting with phosphospecific antibodies indicated that there was little if any effect on the phosphorylation of Ser37, Thr41 or Ser45; however, the phosphorylation of Ser33 appeared to be affected in the beta-catenin mutants. Specifically, antiphospho-beta-catenin 33/37/41 antibody identified high, intermediate and low expression levels of phosphorylated beta-catenin in cells transfected with D32G, D32N and D32Y, respectively. Experiments with the proteosome inhibitor N-acetyl-Leu-Leu-norleucinal (ALLN) revealed ubiquitinated bands on all three mutant beta-catenins, as well as on WT beta-catenin. The relative order of ubiquitination was WT>D32G>D32N>D32Y, in parallel with findings from the phosphorylation studies. These results are discussed in the context of previous studies, which indicated that amino-acid residue D32 lies within the ubiquitination recognition motif of beta-catenin.
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PMID:Phosphorylation and ubiquitination of oncogenic mutants of beta-catenin containing substitutions at Asp32. 1506 18

Diesel exhaust particles (DEP) induce intense inflammatory and allergic immune responses. The epidermal cells receive much exposure to DEP, and are an important source of pro-inflammatory cytokines and other inflammatory mediators. Transcription factors, such as nuclear factor kappa B (NF-kappaB) and activator protein 1 (AP-1), regulate the expression of these mediators. We hypothesize that the transcription factors are target of DEP action. The current study sought to determine whether DEP-activated NF-kappaB and AP-1 in a mouse epidermal cell line, JB6 P(+) cells. Using stable transfectants of JB6 P(+) cells expressing NF-kappaB or AP-1 luciferase reporter constructs, we demonstrated that exposure to DEP at a non-cytotoxic concentration significantly enhanced the transactivation of NF-kappaB, but not AP-1. Furthermore, DEP promoted phosphorylation of Akt, a substrate of phosphatidylinositol 3-kinase (PI3K), on Ser-473 and Thr-308 in a PI3K-dependent manner, and enhanced phosphorylation of down-stream p70/p85 S6 kinases (p70/p85S6K) as well as glycogen synthase kinase-3beta (GSK-3beta). Blockage of PI3K activation eliminated DEP-stimulated NF-kappaB transactivation. Although SAPK/JNK pathway was modestly activated by DEP, it was not involved in NF-kappaB transactivation. DEP had little effect on the phosphorylation of ERKs and p38 MAPK. Thus, DEP-induced transactivation of NF-kappaB is mediated by PI3K/Akt signaling pathway.
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PMID:Activation of nuclear factor kappa B by diesel exhaust particles in mouse epidermal cells through phosphatidylinositol 3-kinase/Akt signaling pathway. 1513 Jul 73

In this study we report a new mechanism whereby cyclic AMP (cAMP) regulates the cell-cycle machinery. We demonstrate that elevation of intracellular levels of cAMP promotes degradation of cyclin D3 in proteasomes, and that this occurs via glycogen synthase kinase-3beta (GSK-3beta)-mediated phosphorylation of cyclin D3 at Thr-283. Elevation of cAMP did not change the subcellular distribution of either cyclin D3 or GSK-3beta. However, cAMP promoted the interaction between cyclin D3 and GSK-3beta both in vitro and in vivo, indicating that GSK-3beta-mediated phosphorylation of cyclin D3 might require the association between the two proteins. These results demonstrate how cAMP enhances degradation of cyclin D3. Furthermore, we provide evidence for a novel mechanism by which GSK-3beta might phosphorylate unprimed substrates in vivo.
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PMID:cAMP-induced degradation of cyclin D3 through association with GSK-3beta. 1525 16

The inositol 5-phosphatase SHIP (SHIP-1) is a negative regulator of signal transduction in hematopoietic cells and targeted disruption of SHIP in mice leads to a myeloproliferative disorder. We analyzed the effects of SHIP on the human leukemia cell line Jurkat in which expression of endogenous SHIP protein is not detectable. Restoration of SHIP expression in Jurkat cells with an inducible expression system caused a 69% reduction of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) and a 65% reduction of Akt kinase activity, which was associated with reduced phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) (Ser-9) without changing the phosphorylation of Bad (Ser-136), FKHR (Ser-256) or MAPK (Thr-202/Tyr-204). SHIP-expressing Jurkat cells showed an increased transit time through the G1 phase of the cell cycle, but SHIP did not cause a complete cell cycle arrest or apoptosis. Extension of the G1 phase was associated with an increased stability of the cell cycle inhibitor p27(Kip1) and reduced phosphorylation of the retinoblastoma protein Rb at serine residue 780. Our data indicate that restoration of SHIP activity in a human leukemia cell line, which has lost expression of endogenous SHIP, downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle.
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PMID:Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle. 1545 86


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