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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxynivalenol (DNV) is the most frequently encountered trichothecene in grain-based foods, and is able to produce toxic effects resulting in various diseases in farm and laboratory animals. The molecular mechanisms that control this mycotoxin mediated effects in porcine endometrial cells are far from being completely understood. Recent results show that DNV inhibits protein synthesis in actively proliferating tissues. Therefore, the present study investigated the effects of this mycotoxin on a cellular level in an in vivo and in vitro system. The abundance and phosphorylation state (activity) of the cell cycle dependent kinases MAPk and Akt (PKB) and their potential targets eIF-4E (eukaryotic initiation factor 4E) and 4E-BP1 (4E binding protein, eIF4E repressor protein) were examined. In previous investigations it was found that these factors are involved in initiation of mRNA translation. The results show that DNV in vitro strongly reduce the abundance of p38 MAPk, protein kinase Akt and the alpha- and beta-4E-BP1 bands. The phosphorylation state of these proteins was obviously not modulated. In contrast, the eIF4E phosphorylation was strongly reduced in DNV treated cells. In summary, our in vitro results let assume that DNV potentially influences gene expression, but this work does not present a direct proof that DNV alters processes, which are involved in the initiation of mRNA translation. Surprisingly in vivo, an influence of DNV feeding on the investigated molecular events could not be demonstrated.
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PMID:In vitro and in vivo effects of deoxynivalenol (DNV) on regulators of cap dependent translation control in porcine endometrium. 1609 39

Recent analyses indicate that the expression of the Pim-1 protein kinase is elevated in biopsies of prostate tumors. To identify the mechanism by which the Pim kinases may affect the growth of prostate tumors, we expressed Pim-1, Pim-2, or a kinase-dead Pim-2 protein in human PC3 prostate cancer cells. On implantation of the transfectants in nude mice, the growth of the cells expressing Pim-1 or Pim-2 was significantly faster than the growth of the control cells transfected with the neomycin-resistant gene or the kinase-dead Pim-2 protein. When grown in medium, the doubling time of the Pim-1 and Pim-2 transfectants was faster (0.75 days) than that of the control cells (1.28 days). We, therefore, examined the ability of Pim to control the phosphorylation of proteins that regulate protein synthesis. On growth factor starvation or rapamycin treatment, the Pim-1 and Pim-2 transfectants maintained their ability to phosphorylate 4E-BP1 and S6 kinase, although this phosphorylation did not occur in the control-transfected PC3 cells. We have found that the cellular levels of c-Myc were elevated in the Pim-1 and Pim-2 transfectants under these conditions. The Pim-1 and Pim-2 transfectants have lower levels of serine/threonine protein phosphatase 2A (PP2A) activity and the alpha- and beta-subunit B56gamma of the PP2A phosphatase do not coimmunoprecipitate in these cells. Thus, the effects of Pim on PP2A activity may mediate the levels of c-Myc and the phosphorylation of proteins needed for increased protein synthesis. Both of these changes could have a significant impact on tumor growth.
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PMID:Pim family kinases enhance tumor growth of prostate cancer cells. 1612 40

In this study, we investigated the effect of age on the association of eukaryotic initiation factor 4E (eIF4E) with eukaryotic initiation factor 4G (eIF4G), as well as the activity of its binding protein (4E-BP1) and the activity of glycogen synthase kinase-3 (GSK-3) after a single bout of rat hindlimb muscle contractile activity elicited by high-frequency electrical stimulation (HFES) of the sciatic nerve. Tibialis anterior (TA) and plantaris (Pla) muscles from adult (Y; 6 mo old) and aged (O; 30 mo old) Fischer 344 x Brown Norway rats were collected immediately or 6 h after HFES. eIF4E-eIF4G association was elevated at 6 h of recovery in TA (1.9 +/- 0.2-fold, P < 0.05) and immediately and 6 h after exercise in Pla (2.1 +/- 0.3- and 2.1 +/- 0.7-fold, P < 0.05) in Y rats. No significant increase was observed in O rats. An increase in 4E-BP1 phosphorylation was observed only 6 h after HFES in TA (5.0 +/- 2.0-fold, P < 0.05) in Y rats. Phosphorylation of GSK-3alpha was increased immediately and 6 h after contraction in TA (1.6 +/- 0.3- and 4.1 +/- 0.8-fold, P < 0.05) and Pla (1.7 +/- 0.2- and 2.1 +/- 0.4-fold, P < 0.05) in Y rats and remained unaffected in O rats. Phosphorylation of GSK-3beta was observed only immediately after HFES in TA (1.5 +/- 0.2-fold, P < 0.05) in Y rats. Overall, eIF4E-eIF4G association and phosphorylation of 4E-BP1 and GSK-3 are increased after HFES in adult, but not in aged, animals. These observations suggest that the anabolic response to muscle stimulation is attenuated with aging and may contribute to the limited capacity of hypertrophy in aged animals.
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PMID:Age-associated decrease in contraction-induced activation of downstream targets of Akt/mTor signaling in skeletal muscle. 1630 59

BCAAs (leucine, isoleucine, and valine), particularly leucine, have anabolic effects on protein metabolism by increasing the rate of protein synthesis and decreasing the rate of protein degradation in resting human muscle. Also, during recovery from endurance exercise, BCAAs were found to have anabolic effects in human muscle. These effects are likely to be mediated through changes in signaling pathways controlling protein synthesis. This involves phosphorylation of the mammalian target of rapamycin (mTOR) and sequential activation of 70-kD S6 protein kinase (p70 S6 kinase) and the eukaryotic initiation factor 4E-binding protein 1. Activation of p70 S6 kinase, and subsequent phopsphorylation of the ribosomal protein S6, is associated with enhanced translation of specific mRNAs. When BCAAs were supplied to subjects during and after one session of quadriceps muscle resistance exercise, an increase in mTOR, p70 S6 kinase, and S6 phosphorylation was found in the recovery period after the exercise with no effect of BCAAs on Akt or glycogen synthase kinase 3 (GSK-3) phosphorylation. Exercise without BCAA intake led to a partial phosphorylation of p70 S6 kinase without activating the enzyme, a decrease in Akt phosphorylation, and no change in GSK-3. It has previously been shown that leucine infusion increases p70 S6 kinase phosphorylation in an Akt-independent manner in resting subjects; however, a relation between mTOR and p70 S6 kinase has not been reported previously. The results suggest that BCAAs activate mTOR and p70 S6 kinase in human muscle in the recovery period after exercise and that GSK-3 is not involved in the anabolic action of BCAAs on human muscle.
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PMID:Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. 1636 96

Heat shock protein 90 (Hsp90) was co-immunoprecipitated with raptor, the binding partner of the mammalian target of rapamycin (mTOR) from HEK293 cells. Hsp90 was detected in the anti-raptor antibody immunoprecipitates prepared from the cell extract by immunoblot analysis using the anti-Hsp90 antibody, and the association of these two proteins was confirmed by immunoprecipitation from the cells co-expressing Hsp90 and raptor as epitope-tagged molecules. Geldanamycin, a potent inhibitor of Hsp90, disrupted the in vivo binding of Hsp90 to raptor without affecting the association of raptor and mTOR, and suppressed the phosphorylation by mTOR of the downstream translational regulators p70 S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The protein kinase activity of S6K as well as the phosphorylation of the substrate, 40S ribosomal protein S6, were lowered in the geldanamycin-treated cells. These results indicate that Hsp90 is involved in the regulation of protein translation by facilitating the phosphorylation reaction of 4E-BP1 and S6K catalyzed by the mTOR/raptor complex through the association with raptor, and that the mTOR signaling pathway is a novel target of geldanamycin.
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PMID:Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin. 1642 28

To investigate the in vivo effects of resistance exercise on translational control in human skeletal muscle, we determined the phosphorylation of AMP-activated kinase (AMPK), eukaryotic initiation factor 4E-binding protein (4E-BP1), p70/p85-S6 protein kinase (S6K1), and ribosomal S6 protein (S6). Furthermore, we investigated whether changes in the phosphorylation of S6K1 are muscle fiber type specific. Eight male subjects performed a single high-intensity resistance exercise session. Muscle biopsies were collected before and immediately after exercise and after 30 and 120 min of postexercise recovery. The phosphorylation statuses of AMPK, 4E-BP1, S6K1, and S6 were determined by Western blotting with phospho-specific and pan antibodies. To determine fiber type-specific changes in the phosphorylation status of S6K1, immunofluorescence microscopy was applied. AMPK phosphorylation was increased approximately threefold immediately after resistance exercise, whereas 4E-BP1 phosphorylation was reduced to 27 +/- 6% of preexercise values. Phosphorylation of S6K1 at Thr421/Ser424 was increased 2- to 2.5-fold during recovery but did not induce a significant change in S6 phosphorylation. Phosphorylation of S6K1 was more pronounced in the type II vs. type I muscle fibers. Before exercise, phosphorylated S6K1 was predominantly located in the nuclei. After 2 h of postexercise recovery, phospho-S6K1 was primarily located in the cytosol of type II muscle fibers. We conclude that resistance exercise effectively increases the phosphorylation of S6K1 on Thr421/Ser424, which is not associated with a substantial increase in S6 phosphorylation in a fasted state.
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PMID:Increase in S6K1 phosphorylation in human skeletal muscle following resistance exercise occurs mainly in type II muscle fibers. 1643 52

The aim of this study was to evaluate the effect of nutritional deprivation (ND) on signal transduction pathways influencing the translational apparatus in the diaphragm muscle. Male rats were divided into two groups: 1) 20% of usual food intake for 4 days (ND) with water provided at libitum and 2) free-eating control (Ctl). Total protein and RNA were extracted from the diaphragm. Insulin-like growth factor I mRNA was analyzed by RT-PCR. Protein analyses of key cytoplasmic proteins for three signaling pathways deemed important in influencing protein turnover [phosphatidylinositol 3-kinase- Akt-mammalian target of rapamycin, P13K/Akt/glycogen synthase kinase (GSK)-3, and MAPK-ERK] were performed by Western blot. Body weight decreased 30% in ND and increased 17% in Ctl animals. Diaphragm mass decreased 29% in ND animals. Muscle insulin-like growth factor I mRNA abundance was reduced 63% in ND animals. ND resulted in a 55% reduction in phosphorylated (Ser473) Akt. Phosphorylation of mammalian target of rapamycin at Ser2448 was reduced by 85% in ND animals. Downstream effectors important in translation initiation were also affected by ND. Phosphorylated (Thr389) 70-kDa ribosomal protein S6 kinase was significantly reduced (35%) by ND. ND also resulted in significant dephosphorylation of the translational repressor initiation factor 4E-binding protein 1. Phosphorylation of GSK-3alpha (Ser21) and GSK-3beta (Ser9) was increased 55 and 45%, respectively, with ND. Phosphorylation of ERK1 (Thr202) and ERK2 (Tyr204), p44 and p42, respectively, was reduced 64 and 55%, respectively, with ND. Total protein concentration for all signaling intermediates of the three pathways was preserved. We conclude that short-term ND altered the phosphorylation states of key proteins of several pathways involved in protein turnover. This forms the framework for future studies aimed at identifying therapeutic targets in the management of short-term nutritionally induced cachectic states.
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PMID:Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover. 1648 60

Insulin- and amino acid-induced signalling by the mammalian target of rapamycin (mTOR) involves hyperphosphorylation of the p70 ribosomal S6 protein kinase (p70S6-kinase) and the eukaryotic initiation factor 4E (eIF4E) binding protein 4E-BP1 and contributes to regulation of protein metabolism. This review considers the impact of cell hydration on mTOR-dependent signalling. Although hypoosmotic hepatocyte swelling in some instances activates p70S6-kinase, the hypoosmolarity-induced proteolysis inhibition in perfused rat liver is insensitive to mTOR inhibition by rapamycin. Likewise, swelling-dependent proteolysis inhibition by insulin and swelling-independent proteolysis inhibition by leucine, a potent activator of p70S6-kinase and 4E-BP1 hyperphosphorylation, in perfused rat liver is insensitive to rapamycin, indicating that at least rapamycin-sensitive mTOR signalling is not involved. Hyperosmotic dehydration in different cell types produces inactivation of signalling components around mTOR, thereby attenuating insulin-induced glucose uptake, glycogen synthesis, and lipogenesis in adipocytes, and MAP-kinase phosphatase MKP-1 expression in hepatoma cells. Direct inactivation of mTOR, stimulation of the AMP-activated protein kinase, and the destabilization of individual proteins may impair mTOR signalling under dehydrating conditions. Further investigation of the crosstalk between the mTOR pathway(s) and hyperosmotic signalling will improve our understanding about the contribution of cell hydration changes in health and disease and will provide further rationale for fluid therapy of insulin-resistant states.
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PMID:Cell hydration and mTOR-dependent signalling. 1673 59

In several cellular systems, amino acids synergize with insulin in promoting protein synthesis through the activation of the protein kinases p70/S6-K and PHAS-1. Such activations are mediated by the upstream kinase: mammalian target of rapamycin (mTor). In this work we have investigated the intracellular pathways involved in insulin-induced and amino acid-induced p70/S6-K activations in human endothelial cells. In human umbilical vein endothelial cells, insulin induces the phosphorylation of p70/S6-K at 5 minutes decreasing thereafter, whereas amino acids alone or associated with insulin phosphorylate p70/S6-K at all the time points analyzed (60 minutes). Insulin and amino acids phosphorylate p70/S6-K by mTor-dependent and phosphotidylinositol 3-kinase-dependent mechanisms, whereas the mitogen-activated protein kinase pathway is involved only when p70/S6-K is activated by insulin. Insulin induces the phosphorylation of Akt and extracellular signal-regulated protein kinase (ERK) 1/2, whereas amino acids did not. Moreover, amino acids suppress the phosphorylations induced by insulin. The inhibitory effects of amino acids are reverted by the mTor inhibitor rapamycin. Insulin-induced phosphorylation of Akt (at 15 and 30 minutes) is not accompanied by the phosphorylation of the downstream kinase p70/S6-K, indicating the existence of a negative feedback at this level. Our data demonstrate that at the level of human endothelial cells, amino acids synergize with insulin in the phosphorylation of the kinase that lies downstream mTor, as p70/S6-K, whereas they inhibit the upstream kinases Akt and extracellular signal-regulated protein kinase 1/2 when activated by insulin, by an mTor-dependent mechanism.
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PMID:In human endothelial cells amino acids inhibit insulin-induced Akt and ERK1/2 phosphorylation by an mTOR-dependent mechanism. 1677 2

Activation of the tumour suppressor protein p53 rapidly inhibits protein synthesis. This is associated with dephosphorylation and cleavage of initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. When the activation of p53 is reversed within 16 h 4E-BP1 becomes rephosphorylated, the level of intact eIF4GI slowly increases and protein synthesis gradually recovers. The recovery of protein synthesis is partially blocked by rapamycin and wortmannin but not by the protein kinase inhibitors PD98059 and CGP74514A. Both rapamycin and wortmannin, but not PD98059 or CGP74514A, delay the reappearance of eIF4GI. In contrast, full-length 4E-BP1 rapidly becomes rephosphorylated and this process is partially inhibited by rapamycin, PD98059 and CGP74514A. Thus, activation of p53 results in the inhibition of distinct rapamycin- and wortmannin-sensitive pathways that target eIF4GI, and rapamycin-sensitive and -insensitive pathways that target 4E-BP1. Following inactivation of p53 the gradual recovery is determined largely by the kinetics of restoration of eIF4GI rather than by the rephosphorylation of full-length 4E-BP1. These findings suggest that the ability of cells to rephosphorylate 4E-BP1, resynthesise eIF4GI and restore the rate of protein synthesis after inactivation of p53 is an important aspect of recovery following the relief of physiological stress.
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PMID:Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53. 1699 Aug 47


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