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)

Multiple myeloma (MM) is a plasma cell malignancy preliminary localized in the bone marrow and characterized by its capacity to disseminate. IL-6 and IGF-1 have been shown to mediate proliferative and anti-apoptotic signals in plasmocytes. However, in primary plasma-cell leukemia (PCL) and in end-stage aggressive extramedullar disease, the cytokine requirement for both effects may be not mandatory. This suggests that constitutive activation of signaling pathways occurs. One of the signaling pathways whose deregulation may play an oncogenic role in MM is the phosphatidylinositol 3-kinase (PI 3-K) pathway. In human growth factor-independent MM cell lines OPM2 and RPMI8226, we show that the PI 3-K inhibitors LY294002 and Wortmannin strongly inhibited cell proliferation, whereas inhibition of the mammalian Target Of Rapamycin (mTOR)/P70-S6-kinase (P70(S6K)) pathway with rapamycin or of the Mitogen-Activated Protein Kinase (MAPK) pathway with PD98059 had minimal effect on proliferation. In both cell lines, constitutive activation of the PI 3-K/Akt/FKHRL-1, mTOR/P70(S6K) and MAPK pathways was detected. LY294002 inhibited phosphorylation of Akt, FKHRL-1 and P70(S6K) but had no effect on ERK1/2 phosphorylation, indicating that the PI 3-K and MAPK pathways are independent. IGF-1 but not IL-6 increased phosphorylation of Akt, FKHRL-1 and P70(S6K). Purified plasmocytes from four patients with MM and two patients with primary PCL were studied. In three of them including the two patients with PCL, constitutive phosphorylation of Akt, FKHRL-1 and P70(S6K) was present, inhibited by LY294002 and enhanced by IGF-1. In these patients with constitutive Akt activation, normal PTEN expression was detected. PI 3-K inhibition induced caspase-dependent apoptosis as confirmed by inhibition with the large spectrum caspase inhibitor Z-VAD-FMK and cleavage of pro-caspase-3. Both cell lines spontaneously expressed Skp2 and cyclin D1 proteins at high levels but no p27(Kip1) protein. In the presence of LY294002, cell-cycle arrest in G0/G1 was observed, p27(Kip1) protein expression was up-regulated whereas the expression of both Skp2 and cyclin D1 dramatically diminished. PI 3-K-dependent GSK-3alpha/beta constitutive phosphorylation was also detected in OPM2 cells that may contribute to high cyclin D1 expression. Overall, our results suggest that PI 3-K has a major role in the control of proliferation and apoptosis of growth factor-independent MM cell lines. Most of the biological effects of PI 3-K activation in these cell lines may be mediated by the opposite modulation of p27(Kip1) and Skp2 protein expression. Moreover, constitutive activation of this pathway is a frequent event in the biology of MM in vivo and may be more frequently observed in PCL.
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PMID:Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. 1224 56

Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase with a broad array of cellular targets, such as cytoskeletal proteins and transcription factors. Recent studies with GSK-3beta-null mice showed impaired NFkappaB-mediated survival responses. Because NFkappaB serves a dual role as a key regulator of cytokine-induced inflammatory gene expression and apoptosis, we investigated whether modulation of GSK-3beta expression affects cytokine-induced and NFkappaB-mediated inflammatory gene expression. We observed that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) treatment of primary cultures of human microvascular cells reduced net endogenous active GSK-3beta protein levels while inducing inflammatory cytokine (IL-6 and monocyte chemoattractant protein-1 (MCP-1)) expression. Interestingly, inhibition of GSK-3beta by antisense oligonucleotides or pharmacological agent (10 mm lithium) potentiated TNF-induced expression of IL-6 and MCP-1 by 2-6-fold suggesting that inhibition of GSK-3beta under inflammatory conditions (exposure to TNF-alpha and IL-1beta) may contribute to enhanced cytokine expression. Overexpression of GSK-3beta in endothelial cells, in contrast, significantly inhibited (by 70%, p < 0.01) both TNF-alpha and IL-1beta-induced expression of IL-6, MCP-1, and vascular cell adhesion molecule-1. Using adenoviruses in lipopolysaccharide-stimulated mice, overexpression of GSK-3beta significantly decreased TNF-alpha expression in lung and heart tissues (38 and 15%, respectively), further confirming the anti-inflammatory role of GSK-3beta. Overexpression of GSK-3beta did not affect the TNF-alpha-induced nuclear translocation of NFkappaB but reduced the nuclear half-life of TNF-alpha-induced NFkappaB considerably (by as much as 9 h) and enhanced phosphorylation (by as much as 33%). Interestingly, neither endothelial cell survival nor NFkappaB-mediated expression of anti-apoptotic genes was affected by GSK-3beta overexpression. We conclude that GSK-3beta selectively regulates NFkappaB-mediated inflammatory gene expression by controlling the flow of NFkappaB activity between transcription of inflammatory and survival genes.
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PMID:Novel anti-inflammatory role for glycogen synthase kinase-3beta in the inhibition of tumor necrosis factor-alpha- and interleukin-1beta-induced inflammatory gene expression. 1660 Nov 13

It has been reported that platelet-derived growth factor (PDGF)-BB stimulates the synthesis of interleukin (IL)-6 in osteoblasts. In the present study, we investigated whether the phosphatidylinositol 3-kinase (PI3K)/Akt is involved in the PDGF-BB-induced IL-6 synthesis in osteoblast-like MC3T3-E1 cells. PDGF-BB markedly induced the phosphorylation of Akt and GSK-3beta. Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, significantly amplified the synthesis of IL-6 by PDGF-BB. The PDGF-BB-induced GSK-3beta phosphorylation was suppressed by the Akt inhibitor. The IL-6 synthesis stimulated by PDGF-BB was markedly enhanced by LY294002 and wortmannin, inhibitors of PI3K. Wortmannin and LY294002 suppressed the PDGF-BB-induced phosphorylation of Akt and GSK-3beta. Taken together, these results strongly suggest that PI3K/Akt negatively regulates the PDGF-BB-stimulated IL-6 synthesis in osteoblasts.
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PMID:Phosphatidylinositol 3-kinase/Akt auto-regulates PDGF-BB-stimulated interleukin-6 synthesis in osteoblasts. 1681 29

The key components of the intracellular molecular network required for the expression of a specific function of dendritic cells (DCs) are as yet undefined. Using an in vitro model of human monocyte-derived DC differentiation, this study investigates the role of glycogen synthase kinase 3 (GSK-3), a multifunctional enzyme critical for cellular differentiation, apoptosis, self-renewal, and motility, in this context. We demonstrate that GSK-3 (1) inhibits macrophage development during differentiation of DCs, (2) is constitutively active in immature DCs and suppresses spontaneous maturation, and (3) acquires a proinflammatory functional status mediating high levels of IL-12, IL-6, and TNF-alpha secretion, and partially inhibits IL-10 in the context of DC activation. In particular, GSK-3 enhances IL-12p35 mRNA expression and thus the production of the proinflammatory cytokine IL-12p70 by integrating the activities of other kinases priming GSK-3 targets and the inhibitory effects of Akt-1. GSK-3 may therefore act as a key integrator of activating and inhibitory pathways involved in proinflammatory DC differentiation and activation.
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PMID:GSK-3 mediates differentiation and activation of proinflammatory dendritic cells. 1703 18

Wild-type (WT) Salmonella typhimurium causes acute intestinal inflammation by activating the nuclear factor kappa B (NF-kappaB) pathway. Interestingly, WT Salmonella infection also causes degradation of beta-catenin, a regulator of cellular proliferation. Regulation of beta-catenin and the inhibitor of NF-kappaB, IkappaBalpha, is strikingly similar, involving phosphorylation at identical sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how beta-catenin directly regulates the NF-kappaB pathway during bacteria-induced inflammation in vivo is unknown. Using streptomycin-pretreated mice challenged with Salmonella, we demonstrated that WT Salmonella stimulated beta-catenin degradation and decreased the physical association between NF-kappaB and beta-catenin. Accordingly, WT Salmonella infection decreased the expression of c-myc, a beta-catenin-regulated target gene, and increased the levels of IL-6 and TNF-alpha, the NF-kappaB-regulated target genes. Bacterial infection directly stimulated phosphorylation of beta-catenin, both in vivo and in vitro. Closer examination revealed that glycogen synthase kinase 3beta (GSK-3beta) kinase activity was increased in response to WT Salmonella, whereas non-virulent Salmonella had no effect. siRNA of GSK-3beta was able to stabilize IkappaBalpha in response to WT Salmonella. Pretreatment for 24 h with LiCl, an inhibitor of GSK-3beta, reduced WT Salmonella induced IL-8 secretion. Additionally, cells expressing constitutively active beta-catenin showed IkappaBalpha stabilization and inhibition of NF-kappaB activity not only after WT Salmonella infection but also after commensal bacteria (Escherichia coli F18) and TNF-alpha treatment. This study suggests a new role for beta-catenin as a negative regulator of inflammation.
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PMID:beta-Catenin activity negatively regulates bacteria-induced inflammation. 1738 65

PKC412 (CGP41251) is a multitarget protein kinase inhibitor with anti-tumor activities. Here, we investigated the effects of PKC412 on macrophages. PKC412 inhibited the proliferation of murine RAW 264.7 macrophages through induction of G2/M cell cycle arrest and apoptosis. At non-toxic drug concentrations, PKC412 significantly suppressed the lipopolysaccharide (LPS)-induced release of TNF-alpha and nitric oxide, while instead enhancing IL-6 secretion. PKC412 attenuated LPS-induced phosphorylations of MKK4 and JNK, as well as AP-1 DNA binding activities. Furthermore, PKC412 suppressed LPS-induced Akt and GSK-3beta phosphorylations. These results suggest that the anti-proliferative and immunomodulatory effects of PKC412 are, at least in part, mediated through its interference with the MKK4/JNK/AP-1 and/or Akt/GSK-3beta pathways. Since macrophages contribute significantly to the development of both acute and chronic inflammation, PKC412 may have therapeutic potential and applications in treating inflammatory and/or autoimmune diseases.
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PMID:PKC412 (CGP41251) modulates the proliferation and lipopolysaccharide-induced inflammatory responses of RAW 264.7 macrophages. 1758 81

Nicotine [(S)-3-(1-methyl-2-pyrrolidinyl)pyridine] is a major component of tobacco and a highly efficient acetylcholine receptor (nAChR) agonist that triggers the cholinergic anti-inflammatory pathway. We demonstrate that pre-treatment of monocytes with the stable nicotine catabolite, cotinine [(S)-1-methyl-5-(3-pyridinyl)-2-pyrrolidinone], dramatically alters the nature of the inflammatory response to Gram negative bacteria by abrogating the production of cytokines that are under the transcriptional control of the NF-kappaB system (TNF-alpha, IL-1beta, IL-6, IL-12/IL-23 p40) and shifting the response towards an IL-10-dominated anti-inflammatory profile. This anti-inflammatory phenomenon is initiated specifically by engagement of the monocytic alpha7 nAChR; and is PI3K/GSK-3beta-dependent; but NF-kappaB-independent. These mechanistic insights suggest an ability to exploit convergent, endogenous anti-inflammatory pathway(s) to either up-regulate or down-regulate the production of specific cytokine groups (pro- or anti-inflammatory cytokines) depending on the clinical necessity.
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PMID:Cotinine-induced convergence of the cholinergic and PI3 kinase-dependent anti-inflammatory pathways in innate immune cells. 1817 63

In rheumatoid arthritis (RA), the synovium is infiltrated by mononuclear cells that influence the proliferation and activation of fibroblast-like synoviocytes (FLS) through soluble mediators as well as cell-to-cell contact. To identify receptor-ligand pairs involved in this cross-talk, we cocultured T cells with FLS lines isolated from synovial tissues from RA patients. Coculture with T cells induced phosphorylation of Akt (Ser(473)) and its downstream mediators, GSK-3alpha/GSK-beta, FoxO1/3a, and mouse double minute-2, and enhanced FLS proliferation. T cell-mediated phospho-Akt up-regulation was unique for FLS as no such effect was observed upon interaction of T cells with dendritic cells and B cells. Akt activation was induced by all functional T cell subsets independent of MHC/Ag recognition and was also found with other leukocyte populations, suggesting the involvement of a common leukocyte cell surface molecule. Akt phosphorylation, enhanced in vitro FLS proliferation, and enhanced FLS IL-6 production was inhibited by blocking Abs to CD11a and ICAM-2 whereas Abs to ICAM-1 had a lesser effect. Selective involvement of the LFA-1-ICAM-2 pathway was confirmed by the finding of increased ezrin phosphorylation at Tyr(353) that is known to be downstream of ICAM-2 and supports cell survival through Akt activation. CD28(-) T cells, which are overrepresented in RA patients, have high CD11a cell surface expression and induce Akt phosphorylation in FLS more potently than their CD28(+) counterparts. These findings identify ICAM-2 as a potential therapeutic target to inhibit FLS activation in RA, allowing for a more selective intervention than broad LFA-1 inhibition.
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PMID:Synoviocyte stimulation by the LFA-1-intercellular adhesion molecule-2-Ezrin-Akt pathway in rheumatoid arthritis. 1820 96

Insulin resistance in skeletal muscle is an early event in the development of diabetes, with obesity being one of the major contributing factors. In vitro, conditioned medium (CM) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells, but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process. CM induced insulin resistance in human myotubes at the level of insulin-stimulated Akt and GSK-3 phosphorylation. In addition, insulin-resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD. However, insulin resistance was not paralleled by increased apopotosis. Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling. However, the expression level of myogenin could not be reestablished. In addition to decreasing myogenin expression, CM also decreased the release of IL-6 and IL-8 and increased monocyte chemotactic protein-1 (MCP-1) secretion from skeletal muscle cells. Although regeneration of myotubes reestablished normal secretion of IL-6, the release of IL-8 and MCP-1 remained impaired for 48 h after withdrawal of CM. In conclusion, our data show that insulin resistance in skeletal muscle cells is only partially reversible. Although some characteristic features of insulin-resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM, others such as IL-8 and MCP-1 secretion and myogenin expression remain impaired over a longer period. Thus, we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells.
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PMID:Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility. 1836 60

Deregulated production of cytokines, including IL-1beta, IL-6 and TNF plays an important role in chronic inflammation. Relevant to this condition, direct cellular contact with stimulated T cells is a potent inducer of cytokine production in human monocytes/macrophages. We previously demonstrated that PI3Ks regulate differential production of IL-1beta and its specific inhibitor secreted IL-1 receptor antagonist (sIL-1Ra) by human monocytes. Here we show that in contrast with PI3Kalpha, beta and gamma, PI3Kdelta accounts for most of the PI3K-dependent signaling ruling the production of IL-1beta, IL-6, TNF and sIL-1Ra in monocytes activated by cellular contact with stimulated T cells (mimicked by CHAPS-solubilized membranes of stimulated T cells, CE sHUT) and lipopolysaccharides (LPS); the latter stimuli being relevant to chronic/sterile and acute/infectious inflammation, respectively. Interestingly, PI3Kdelta activity dampened the production of pro-inflammatory cytokines in LPS-activated monocytes, but induced it in CE sHUT-activated cells. In both CE sHUT- and LPS-activated monocytes PI3Kdelta regulated cytokine transcript expression through the phosphorylation/inactivation of glycogen synthase kinase-3beta (GSK3beta). The blockade of GSK3beta displayed inverse effects to those of PI3Kdelta blockade. Thus, by displaying opposite functions in conditions mimicking chronic/sterile and acute/infectious inflammation, i.e., by repressing pro-inflammatory cytokine expression in LPS-activated monocytes but inducing such mediators in T cell contact-activated monocytes, PI3Kdelta represents a potential therapeutic target specific to chronic/sterile inflammatory conditions.
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PMID:Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions. 1847 82


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