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)

c-Myc is a nuclear phosphoprotein which binds DNA as a heterodimer with Max. We have identified two in vivo phosphorylation sites, Thr58 and Ser62, within a domain highly conserved among all Myc family members. Thr58 is mutated in several viral forms of the protein and constitutes a mutational hot-spot in Burkitt's lymphoma. Members of the GSK-3 and MAP kinase families, but not CKII, specifically phosphorylated these sites in vitro. The effect of these phosphorylation sites on Myc function was assessed by cotransformation of primary rat embryo fibroblasts with Ras. Mutagenesis of Thr58 to alanine potentiated focus formation, whereas substitution of Ser62 severely inhibited transformation. Mutation of both residues restored wild-type activity. These data suggest acute, post-translational modulation of Myc via phosphorylation of a conserved region previously implicated in transactivation, transformation and autorepression.
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PMID:Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo. 830 4

Carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 1,2-dimethylhydrazine (DMH) induce colon tumors in the rat that contain mutations in beta-catenin, but the pattern of mutation differs from that found in human colon cancers. In both species, mutations affect the glycogen synthase kinase-3beta consensus region of beta-catenin, but whereas they directly substitute critical Ser/Thr phosphorylation sites in human colon cancers, the majority of mutations cluster around Ser33 in the rat tumors. Two dietary phytochemicals, chlorophyllin and indole-3-carbinol, given post-initiation, shifted the pattern of beta-catenin mutations in rat colon tumors induced by IQ and DMH. Specifically, 17/39 (44%) of the beta-catenin mutations in groups given carcinogen plus modulator were in codons 37, 41 and 45, and substituted critical Ser/Thr residues directly, as seen in human colon cancers. None of the tumors from groups given carcinogen alone had mutations in these codons. Interestingly, many of the mutations that substituted critical Ser/Thr residues in beta-catenin were from a single group given DMH and 0.001% chlorophyllin, in which a statistically significant increase in colon tumor multiplicity was observed compared with the group given DMH only. These tumors had marked over-expression of cyclin D1, c-myc and c-jun mRNA and c-Myc and c-Jun proteins were strongly elevated compared with tumors containing wild-type beta-catenin. The results indicate that the pattern of beta-catenin mutations in rat colon tumors can be influenced by exposure to dietary phytochemicals administered post-initiation, and that the mechanism might involve the altered expression of beta-catenin/Tcf/Lef target genes.
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PMID:beta-Catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol. 1118 54

Differentiating osteoblasts in culture undergo a commitment stage, during which cobblestone-like cells grow to high density past confluency. In contrast to earlier proliferative stages, the cell cycle during this commitment stage is inhibited by glucocorticoids (GC). Chronic GC treatment also impedes mineral deposition if steroid administration commences early enough during commitment. This study defines a role for glycogen synthase kinase-3beta (GSK3beta) and its target, c-Myc, in the GC-sensitive osteoblast persistent cell cycle. c-Myc levels decreased as cells reached confluence, but then increased during growth to high density. GC administration at this stage resulted in down-regulation of c-Myc. This was accompanied by GC-mediated attenuation of GSK3beta Ser(9) inhibitory phosphorylation and increased GSK3beta kinase activity. Down-regulation of c-Myc was attributable to enhanced Thr(58) phosphorylation, leading to accelerated degradation. In contrast, GC did not inhibit the c-Myc synthesis rate or the level of beta-catenin, a transcriptional coactivator of c-myc. The attenuated cell cycle and the reduced c-Myc level were returned to control levels by specific inhibition of GSK3beta using lithium chloride. These results suggest that tonal GSK3beta repression at the cobblestone stage of osteoblast differentiation permits osteoblast growth to high density. GC interfere with this growth-permissive axis by GSK3beta activation, resulting in c-Myc down-regulation and impediment of the G(1)/S cell cycle transition.
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PMID:Glucocorticoids inhibit cell cycle progression in differentiating osteoblasts via glycogen synthase kinase-3beta. 1187 89

Activation of the Gi protein-coupled A3 adenosine receptor (A3AR) has been implicated in the inhibition of melanoma cell growth by deregulating protein kinase A and key components of the Wnt signaling pathway. Receptor activation results in internalization/recycling events that play an important role in turning on/off receptor-mediated signal transduction pathways. Thus, we hereby examined the association between receptor fate, receptor functionality, and tumor growth inhibition upon activation with the agonist 1-deoxy-1-[6-[[(3-iodophenyl)-methyl]amino]-9H-purine-9-yl]-N-methyl-beta-D-ribofuranuronamide (IB-MECA). Results showed that melanoma cells highly expressed A3AR on the cell surface, which was rapidly internalized to the cytosol and "sorted" to the endosomes for recycling and to the lysosomes for degradation. Receptor distribution in the lysosomes was consistent with the down-regulation of receptor protein expression and was followed by mRNA and protein resynthesis. At each stage, receptor functionality was evidenced by the modulation in cAMP level and the downstream effectors protein kinase A, glycogen synthase kinase-3beta, c-Myc, and cyclin D1. The A3AR antagonist MRS 1523 counteracted the internalization process as well as the modulation in the expression of the signaling proteins, demonstrating that the responses are A3AR-mediated. Supporting this notion are the in vivo studies showing tumor growth inhibition upon IB-MECA treatment and reverse of this response when IB-MECA was given in combination with MRS 1523. In addition, in melanoma tumor lesions derived from IB-MECA-treated mice, the expression level A3AR and the downstream key signaling proteins were modulated in the same pattern as was seen in vitro. Altogether, our observations tie the fate of A3AR to modulation of downstream molecular mechanisms leading to tumor growth inhibition both in vitro and in vivo.
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PMID:A3 adenosine receptor activation in melanoma cells: association between receptor fate and tumor growth inhibition. 1286 31

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

The small GTPase RhoB suppresses cancer in part by limiting cell proliferation. However, the mechanisms it uses to achieve this are poorly understood. Recent studies link RhoB to trafficking of Akt, which through its regulation of glycogen synthase kinase-3 (GSK-3) has an important role in controlling the stability of the c-Myc oncoprotein. c-Myc stabilization may be a root feature of human tumorigenesis as it phenocopies an essential contribution of SV40 small T antigen in human cell transformation. In this study we show that RhoB directs efficient turnover of c-Myc in established or transformed mouse fibroblasts and that the attenuation of RhoB which occurs commonly in human cancer is a sufficient cause to elevate c-Myc levels. Increased levels of c-Myc elicited by RhoB deletion increased the proliferation of nullizygous cells, whereas restoring RhoB in null cells decreased the stability of c-Myc and restrained cell proliferation. Mechanistic analyses indicated that RhoB facilitated nuclear accumulation of GSK-3 and GSK-3-mediated phosphorylation of c-Myc T58, the critical site for ubiquitination and degradation of c-Myc. RhoB deletion restricted nuclear localization of GSK-3, reduced T58 phosphorylation, and stabilized c-Myc. These effects were not associated with changes in phosphorylation or localization of Akt, however, differences were observed in phosphorylation and localization of the GSK-3 regulatory Akt-related kinase, serum- and glucocorticoid-inducible protein kinase (SGK). The ability of RhoB to support GSK-3-dependent turnover of c-Myc offers a mechanism by which RhoB acts to limit the proliferation of neoplastically transformed cells.
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PMID:RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3. 1624 49

Phosphorylation of c-Myc on threonine 58 (T58) stimulates its degradation by the Fbw7-SCF ubiquitin ligase. We used a phosphorylation-specific antibody raised against the c-Myc T58 region to attempt to identify other proteins regulated by the Fbw7 pathway. We identified two predominant proteins recognized by this antibody. The first is Ebna1 binding protein 2, a nucleolar protein that, in contrast with a previous report, is likely responsible for the nucleolar staining exhibited by this antibody. The second is Zcchc8, a nuclear protein that is highly phosphorylated in cells treated with nocodazole. We show that Zcchc8 is directly phosphorylated by GSK-3 in vitro and that GSK-3 inhibition prevents Zcchc8 phosphorylation in vivo. Moreover, we found that Zcchc8 interacts with proteins involved in RNA processing/degradation. We suggest that Zcchc8 is a GSK-3 substrate with a role in RNA metabolism.
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PMID:Zcchc8 is a glycogen synthase kinase-3 substrate that interacts with RNA-binding proteins. 1626 84

We have shown that endogenous activation of type 5 metabotropic glutamate (mGlu5) receptors supports the maintenance of a pluripotent, undifferentiated state in D3 mouse embryonic stem cells cultured in the presence of leukaemia inhibitory factor (LIF). Here, we examined the interaction between LIF and mGlu5 receptors using as a read-out the immediate early gene, c-Myc. The selective mGlu5 receptor antagonist, 2-methyl-6-(phenylenthynyl)pyridine (MPEP; 1 mum), reduced the increase in c-Myc protein levels induced by LIF by enhancing c-Myc ubiquitination. A reduction in c-Myc levels was also observed following small interfering RNA-mediated mGlu5 receptor gene silencing. MPEP reduced glycogen synthase kinase-3beta phosphorylation on Ser9, but increased phosphorylation of the phosphatidylinositol-3-kinase (PI-3-K) substrate, AKT. In our hands, activated PI-3-K reduced the stability of c-Myc, because (i) the PI-3-K inhibitor, LY294002, prevented the reduction in c-Myc levels induced by MPEP; and (ii) over-expression of AKT promoted c-Myc ubiquitination. All effects of MPEP were mimicked by protein kinase C (PKC) inhibitors and reversed by the PKC activator, tetradecanoylphorbol-13-acetate. We conclude that endogenous activation of mGlu5 receptors sustains the increase in c-Myc induced by LIF in embryonic stem cells by inhibiting both glycogen synthase kinase-3beta and PI-3-K, both effects resulting from the activation of PKC.
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PMID:Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increase in c-Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells. 1698 52

Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin's lymphoma, which is associated with infection by Kaposi's sarcoma herpesvirus (KSHV)/human herpesvirus-8. The c-Myc transcription factor plays an important role in cellular proliferation, differentiation and apoptosis. Lymphomas frequently have deregulated c-Myc expression owing to chromosomal translocations, amplifications or abnormal stabilization. However, no structural abnormalities were found in the c-myc oncogene in PEL. Given that c-Myc is often involved in lymphomagenesis, we hypothesized that it is deregulated in PEL. We report that PEL cells have abnormally stable c-Myc protein. The turnover of c-Myc protein is stringently regulated by post-transcriptional modifications, including phosphorylation of c-Myc threonine 58 (T58) by glycogen synthase kinase-3beta (GSK-3beta). Our data show that the impaired c-Myc degradation in PEL cells is associated with a significant underphosphorylation of c-Myc T58. The KSHV latency-associated nuclear antigen (LANA) is responsible for this deregulation. Overexpression of LANA in human embryonic kidney 293 or peripheral blood B cells leads to post-transcriptional deregulation of c-Myc protein. Conversely, when LANA is eliminated from PEL cells using RNA interference, GSK-3beta-mediated c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3beta-containing complexes in PEL cells further confirms the significance of these interactions in naturally KSHV-infected cells.
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PMID:Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen. 1731 Sep 99

Although fatty acids enhance preadipocyte differentiation in the presence of adequate hormone cocktails, little is known regarding their effects in the absence of these hormones. We have now shown that palmitate, a common long-chain saturated fatty acid, induced apoptosis in both mouse 3T3-L1 and rat primary preadipocytes grown in a normal serum-containing medium. Treatment of preadipocytes with palmitate induced multiple endoplasmic reticulum (ER) stress responses, evidenced by increased protein content of CHOP and GRP78 and splicing of XBP-1 mRNA, as well as altered phosphorylation of eIF2alpha and increased phosphorylation of JNK and Erk1/2. Intriguingly, palmitate induced an early activation of Akt but diminished both Akt activation and its protein mass after prolonged incubation (>6 h). In association with these changes, palmitate reduced expression of beta-catenin and its downstream target, c-Myc and cyclin D1, two key prosurvival proteins. Overexpression of constitutively active Akt did not block the apoptotic effect of palmitate. Cotreatment with unsaturated fatty acids (oleate, linoleate) or with LiCl (a glycogen synthase kinase-3beta inhibitor) attenuated the palmitate-induced apoptosis. Subsequent analysis suggested that the unsaturated fatty acids probably counteracted palmitate by reducing, not eliminating, ER stress, whereas LiCl probably improved viability by activating the Wnt signaling pathway. Cotreatment of palmitate with a standard adipogenic hormone cocktail also abolished the apoptotic effect and promoted adipocyte differentiation. Collectively, our results suggest that palmitate causes multiple cellular stresses that may lead to apoptosis in preadipocytes in the absence of adipogenic stimuli, highlighting the importance of exogenous hormones in directing cell fate in response to increased fatty acid influx.
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PMID:Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes. 1751 82


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