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)

Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G(0)-G(1) phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3beta. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth.
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PMID:Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. 1935 20

Growth hormone (GH) and IGF-I have been implicated in the pathogenesis of type I diabetic (DM) nephropathy. We investigated renal GH receptor (GHR) and IGF-type 1 receptor (IGF1R) signaling in an animal model of type I DM. Kidney tissue was examined for GHR and IGF1R key signaling molecules. GHR levels were unchanged and IGF-I mRNA levels were decreased in the diabetic group (D). Basal and GH stimulated phosphorylated (p-) JAK2 and STAT5 levels were similar in controls (C) and D. The levels of p-IGF1R were similar in the two groups at baseline, while pAkt, pGSK3, p-mTOR, p-rpS6, p-erk1/2 (Mapk), and pSTAT-3 were increased in D. Following IGF-I administration p-Akt, p-rpS6, p-Mapk, and p-GSK levels increased more pronouncedly in D versus C. In conclusion, the lack of JAK2-STAT5 activation and the decrease in kidney IGF-I mRNA levels in D argue against a role for the GH activated JAK2-STAT5 pathway in the pathogenesis of diabetic nephropathy. On the other hand while IGF1R phosphorylation was unchanged, Akt/mTOR and MAPK signaling were hyperactivate in DM, suggesting their involvement. The increase in baseline activated Akt, mTOR, rpS6, and MAPK cannot be explained by activation of the IGF1R, but may be triggered by other growth factors and nutrients.
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PMID:Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation. 1938 75

Chronic complete spinal cord injury (SCI) is associated with severe skeletal muscle atrophy as well several atrophy and physical-inactivity-related comorbidity factors such as diabetes, obesity, lipid disorders, and cardiovascular diseases. Intracellular mechanisms associated with chronic complete SCI-related muscle atrophy are not well understood, and thus their characterization may assist with developing strategies to reduce the risk of comorbidity factors. Therefore, the aim of this study was to determine whether there was an increase in catabolic signaling targets, such as atrogin-1, muscle ring finger-1 (MuRF1), forkhead transcription factor (FoXO), and myostatin, and decreases in anabolic signaling targets, such as insulin-like growth factor (IGF), v-akt murine thymoma viral oncogene (Akt), glycogen synthase kinase-beta (GSK-3beta), mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and p70(s6kinase) in chronic complete SCI patients. In SCI patients, when compared with controls, there was a significant reduction in mRNA levels of atrogin-1 (59%; P < 0.05), MuRF1 (55%; P < 0.05), and myostatin (46%; P < 0.01), and in protein levels of FoXO1 (72%; P < 0.05), FoXO3a (60%; P < 0.05), and atrogin-1 (36%; P < 0.05). Decreases in the protein levels of IGF-1 (48%; P < 0.001) and phosphorylated GSK-3beta (54%; P < 0.05), 4E-BP1 (48%; P < 0.05), and p70(s6kinase) (60%; P = 0.1) were also observed, the latter three in an Akt- and mTOR-independent manner. Reductions in atrogin-1, MuRF1, FoXO, and myostatin suggest the existence of an internal mechanism aimed at reducing further loss of muscle proteins during chronic SCI. The downregulation of signaling proteins that regulate anabolism, such as IGF, GSK-3beta, and 4E-BP1, would reduce the ability to increase protein synthesis rates.
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PMID:Atrogin-1, MuRF1, and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients. 1953 53

Several studies have implicated the renin angiotensin system in the cardiac hypertrophy induced by thyroid hormone. However, whether Angiotensin type 1 receptor (AT1R) is critically required to the development of T3-induced cardiomyocyte hypertrophy as well as whether the intracellular mechanisms that are triggered by AT1R are able to contribute to this hypertrophy model is unknown. To address these questions, we employed a selective small interfering RNA (siRNA, 50 nM) or an AT1R blocker (Losartan, 1 microM) to evaluate the specific role of this receptor in primary cultures of neonatal cardiomyocytes submitted to T3 (10 nM) treatment. The cardiomyocytes transfected with the AT1R siRNA presented reduced mRNA (90%, P < 0.001) and protein (70%, P < 0.001) expression of AT1R. The AT1R silencing and the AT1R blockade totally prevented the T3-induced cardiomyocyte hypertrophy, as evidenced by lower mRNA expression of atrial natriuretic factor (66%, P < 0.01) and skeletal alpha-actin (170%, P < 0.01) as well as by reduction in protein synthesis (85%, P < 0.001). The cardiomyocytes treated with T3 demonstrated a rapid activation of Akt/GSK-3beta/mTOR signaling pathway, which was completely inhibited by the use of PI3K inhibitors (LY294002, 10 microM and Wortmannin, 200 nM). In addition, we demonstrated that the AT1R mediated the T3-induced activation of Akt/GSK-3beta/mTOR signaling pathway, since the AT1R silencing and the AT1R blockade attenuated or totally prevented the activation of this signaling pathway. We also reported that local Angiotensin I/II (Ang I/II) levels (120%, P < 0.05) and the AT1R expression (180%, P < 0.05) were rapidly increased by T3 treatment. These data demonstrate for the first time that the AT1R is a critical mediator to the T3-induced cardiomyocyte hypertrophy as well as to the activation of Akt/GSK-3beta/mTOR signaling pathway. These results represent a new insight into the mechanism of T3-induced cardiomyocyte hypertrophy, indicating that the Ang I/II-AT1R-Akt/GSK-3beta/mTOR pathway corresponds to a potential mediator of the trophic effect exerted by T3 in cardiomyocytes.
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PMID:Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway. 1958 83

Shiga toxin 1 (Stx1) transiently increases the expression of proinflammatory cytokines by macrophage-like THP-1 cells in vitro. Increased cytokine production is partly due to activation of the translation initiation factor eIF4E through a mitogen-activated protein kinase (MAPK)- and Mnk1-dependent pathway. eIF4E availability for translation initiation is regulated by association with eIF4E binding proteins (4E-BP). In this study, we showed that Stx1 transiently induced 4E-BP hyperphosphorylation, which may release eIF4E for translation initiation. Phosphorylation of 4E-BP at priming sites T37 and T46 was not altered by Stx1 but was transiently increased at S65, concomitant with increased cytokine expression. Using kinase inhibitors, we showed that 4E-BP phosphorylation was dependent on phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) activation but did not require MAPKs. Stx1 treatment resulted in increased levels of cytosolic Ca(2+). PI3K and Akt activation led to the phosphorylation and inactivation of the positive cytokine regulator glycogen synthase kinase 3alpha/beta (GSK-3alpha/beta). PI3K, Akt, and mTOR inhibitors and small interfering RNA knockdown of Akt expression all increased, whereas a GSK-3alpha/beta inhibitor decreased, Stx1-induced soluble tumor necrosis factor alpha and interleukin-1beta production. Overall, these findings suggest that despite transient activation of 4E-BP, the PI3K/Akt/mTOR pathway negatively influences cytokine induction by inactivating the positive regulator GSK-3alpha/beta.
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PMID:Shiga toxin 1-induced proinflammatory cytokine production is regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway. 1959 74

This study is the first study to investigate the anticancer effect of 6-shogaol in human non-small cell lung cancer A549 cells. 6-Shogaol inhibited cell proliferation by inducing autophagic cell death, but not, predominantly, apoptosis. Pretreatment of cells with 3-methyladenine (3-MA), an autophagy inhibitor, suppressed 6-shogaol mediated antiproliferation activity, suggesting that induction of autophagy by 6-shogaol is conducive to cell death. We also found that 6-shogaol inhibited survival signaling through the AKT/mTOR signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin (mTOR), forkhead transcription factors (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). Phosphorylation of both of mTOR's downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased 6-shogaol mediated autophagic cell death, supporting inhibition of AKT beneficial to autophagy. Moreover, reduction of AKT expression by siRNA potentiated 6-shogaol's effect, also supporting inhibition of AKT beneficial to autophagy. Taken together, these findings suggest that 6-shogaol may be a promising chemopreventive agent against human non-small cell lung cancer.
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PMID:6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. 1979 25

To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulin-induced Akt Thr(308) and its immediate downstream substrate GSK-3alpha/beta in a time-dependent fashion, with approximately 70% reduction at 15 min. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser(636)/Ser(639) that was prevented by selective blockade of EGFR tyrosine kinase activity with AG1478. Previous studies have shown that insulin-induced phosphorylation of IRS-1 on Ser(636)/Ser(639) is mediated mainly by the PI3K/mTOR/S6K-1 sequence. Studies with specific inhibitors of PI3K (wortmannin) and mTOR (rapamycin) revealed that Ang II stimulates IRS-1 phosphorylation of Ser(636)/Ser(639) via the PI3K/mTOR/S6K-1 pathway. Both inhibitors blocked the effect of Ang II on insulin-induced activation of Akt. Studies using the specific MEK inhibitor, PD98059, revealed that ERK1/2 activation also mediates Ang II-induced S6K-1 and IRS-1 phosphorylation, and the impairment of Akt Thr(308) and GSK-3alpha/beta phosphorylation. Further studies with selective inhibitors showed that PI3K activation was upstream of ERK, suggesting a new mechanism for Ang II-induced impairment of insulin signaling. These findings indicate that Ang II has a significant role in the development of insulin resistance by a mechanism that involves EGFR transactivation and the PI3K/ERK1/2/mTOR-S6K-1 pathway.
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PMID:Angiotensin-induced EGF receptor transactivation inhibits insulin signaling in C9 hepatic cells. 1987 50

Hematopoietic stem cell (HSC) homeostasis depends on the balance between self renewal and lineage commitment, but what regulates this decision is not well understood. Using loss-of-function approaches in mice, we found that glycogen synthase kinase-3 (Gsk3) plays a pivotal role in controlling the decision between self renewal and differentiation of HSCs. Disruption of Gsk3 in BM transiently expanded phenotypic HSCs in a betta-catenin-dependent manner, consistent with a role for Wnt signaling in HSC homeostasis. However, in assays of long-term HSC function, disruption of Gsk3 progressively depleted HSCs through activation of mammalian target of rapamycin (mTOR). This long-term HSC depletion was prevented by mTOR inhibition and exacerbated by betta-catenin knockout. Thus, GSK-3 regulated both Wnt and mTOR signaling in mouse HSCs, with these pathways promoting HSC self renewal and lineage commitment, respectively, such that inhibition of Gsk3 in the presence of rapamycin expanded the HSC pool in vivo. These findings identify unexpected functions for GSK-3 in mouse HSC homeostasis, suggest a therapeutic approach to expand HSCs in vivo using currently available medications that target GSK-3 and mTOR, and provide a compelling explanation for the clinically prevalent hematopoietic effects observed in individuals prescribed the GSK-3 inhibitor lithium.
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PMID:Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. 1995 76

The 21st international symposium of the American Association for Cancer Research (AACR), the NCI and the European Organization for Research and Treatment of Cancer (EORTC), held in Boston, included topics covering the development of therapeutics and molecular targets in the field of cancer research. This conference report highlights selected presentations on the development of novel drugs for cancer. Investigational drugs discussed include RO-506876 (F Hoffmann-La Roche Ltd), GDC-0980 (Genentech Inc), EMD-1214063 and EMD-1204831 (Merck Serono SA), AR-mTOR01 and AR-mTOR-26 (Array BioPharma Inc), GSK-2126458 (GlaxoSmithKline plc), EXEL-1415 and EXEL-2008 (Exelixis Inc), FP-1039 (FivePrime Therapeutics Inc), and AV-412 (AVEO Pharmaceuticals Inc).
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PMID:AACR-NCI-EORTC--21st International Symposium. Molecular targets and cancer therapeutics--Part 2. 2002 39

Activation of the beta-catenin and receptor kinase pathways occurs often in medulloblastoma, the most common pediatric malignant brain tumor. In this study, we show that molecular cross-talk between the beta-catenin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways is crucial to sustain medulloblastoma pathophysiology. Constitutive activation of phosphoinositide-dependent protein kinase 1 (PDK1), Akt, and phosphorylation of [corrected] glycogen synthase kinase 3beta (GSK-3beta) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by activation [corrected] of GSK-3beta, [corrected] resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner. In vivo, OSU03012 inhibited the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779. These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease.
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PMID:Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. 2002 53


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