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)

The p50 subunit of NF-kappa B is derived from the amino terminus of a 105 kilodalton precursor. The p105 carboxyl terminus, which contains ankyrin-like repeats, a feature of I kappa B molecules, regulates the cytoplasmic retention of p105 and inhibits DNA binding by the precursor. Here, we describe an I kappa B protein identical to the carboxyl-terminal region of p105. Probes spanning the COOH terminus but not the rel homology domain of p105 hybridize to a distinct 2.6-kilobase mRNA expressed in a wide range of murine tissues. The nucleotide sequence of complementary DNA clones for this transcript, in vitro translation, and immune precipitation of metabolically labeled cell lysates establish that it encodes a 70 kilodalton protein that corresponds to the COOH-terminal 607 amino acids of p105. p70 suppresses p65 and p75c-rel mediated transactivation of reporter genes under the control of NF-kappa B elements and in vitro can prevent DNA binding of p50 and p75c-rel homodimers to NF-kappa B sites. The ability of p70 to stably associate with p49 and p65 in vitro, but not inhibit DNA binding by these proteins, suggests that the specific inhibitory properties of this I kappa B may reflect its relative affinity for different rel targets. p70 phosphorylated by protein kinase A fails to inhibit DNA binding by p50 or the c-rel protein, and sequencing of radiolabeled p70 tryptic phosphopeptides establishes that protein kinase A phosphorylates serine residue 576 of p70. This finding suggests that the inhibitory activity of p70 can be regulated by signaling via the adenylate cyclase pathway.
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PMID:The activity of a 70 kilodalton I kappa B molecule identical to the carboxyl terminus of the p105 NF-kappa B precursor is modulated by protein kinase A. 839 3

Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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PMID:Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. 852 13

An active ribosomal protein S6 kinase has been highly purified from the membranes of rabbit reticulocytes by chromatography of the Triton X-100 extract on DEAE-cellulose, SP-Sepharose Fast Flow, and by FPLC on Mono Q and Superose-12. The S6 kinase elutes around 40 000 daltons upon gel filtration on Superose-12 or Sephacryl S-200. It has a subunit molecular weight of 40-43 kDa as determined by protein kinase activity following denaturation/renaturation in SDS-polyacrylamide gels containing S6 peptide. It also phosphorylates translational initiation factors eIF-2 and eIF-4F, glycogen synthase, histone 1, histone 2B, myelin basic protein, but not prolactin, skeletal myosin light chain, histone 4, tubulin, and casein. Apparent Km values have been determined to be 15 microM for ATP, 1.2 microM for S6 and 10 microM for S6 peptide. Two-dimensional tryptic phosphopeptide mapping shows the same sites on S6 are phosphorylated as those identified previously with proteolytically activated multipotential S6 kinase from rabbit reticulocytes, previously denoted as protease activated kinase II. Examination of relative rates of phosphorylation and kinetic constants of synthetic peptides based on previously identified phosphorylation sites, indicates a minimum substrate recognition sequence to be arginine at the n - 3 position. Based on these characteristics, including molecular weight and an expanded substrate specificity, the membrane S6 kinase can be distinguished from the p90 (Type I) and p70 (Type II) S6 kinases, and from protein kinase C and the catalytic subunit of cAMP-dependent protein kinase.
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PMID:A membrane-bound protein kinase from rabbit reticulocytes is an active form of multipotential S6 kinase. 859 70

Cell proliferation requires the co-ordinate triggering of several protein kinases of Ser/Thr specificity such as p70 S6 kinase (S6K), which phosphorylates the ribosomal S6 protein and thus increases translation of mRNAs with polypyrimidine tracts. The multiplicity of signaling pathways leading to p70 S6K activation are not fully elucidated. However, several reports have indicated that the activation of p70 S6K is independent of mitogen-activated protein kinase (MAPK) activation. Interestingly, we and others have shown that constitutive activation of the MAPK pathway promotes cell proliferation, suggesting that this cascade is able to activate p70 S6K, a key step to trigger cell cycle entry. In this report we demonstrate that transfection of constitutively active mitogen-activated protein kinase kinase 1 in CCL 39 cells leads to activation of p70 S6K. Furthermore, we have established a cell line that stably expresses DeltaRaf-1:ER, an estradiol-regulated form of oncogenic Raf-1. The addition of estradiol to these cells was sufficient to elicit rapid activation of mitogen-activated protein kinase kinase 1, MAPK, and p70 S6K. Surprisingly, the activation of p70 S6K is not mediated by MAPK because blocking MAPK activation by expression of the phosphatase MKP-1 did not prevent p70 S6K activation by DeltaRaf-1:ER. In conclusion, we have demonstrated that activation of p70 S6K by DeltaRaf-1:ER is mediated by a new MAPK-independent pathway. This pathway is resistant to low nanomolar concentrations of wortmannin, indicating that it does not involve membrane-bound phosphatidylinositol-trisphosphate kinase activation.
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PMID:Oncogenic Raf-1 activates p70 S6 kinase via a mitogen-activated protein kinase-independent pathway. 866 20

The hexokinases, by converting glucose to glucose 6-phosphate, help maintain the glucose concentration gradient that results in the movement of glucose into cells through the facilitative glucose transporters. Hexokinase II (HKII) is the major hexokinase isoform in skeletal muscle, heart, and adipose tissue. Insulin induces HKII gene transcription in L6 myotubes, and this, in turn, increases HKII mRNA and the rates of HKII protein synthesis and glucose phosphorylation in these cells. Inhibitors of distinct insulin signaling pathways were used to dissect the molecular mechanism by which HKII gene expression is induced by insulin in L6 myotubes. Treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), or with rapamycin, an inhibitor of the pathway from the insulin receptor to p70/p85 ribosomal S6 protein kinase (p70(s6k)), prevented the induction of HKII mRNA by insulin. In contrast, treatment with PD98059, an inhibitor of mitogen-activated protein kinase activation, had no effect on insulin-induced HKII mRNA. In addition, rapamycin blocked the insulin-induced expression of an HKII promoter-chloramphenicol acetyltransferase fusion gene transiently transfected into L6 myotubes, whereas PD98059 had no such effect. These results suggest that a phosphatidylinositol 3-kinase/p70(s6k)-dependent pathway is required for regulation of HKII gene transcription by insulin and that the Ras-mitogen-activated protein kinase-dependent pathway is probably not involved.
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PMID:Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. 866 15

Glucocorticoids (GC) are potent immunosuppressive agents that interfere with interleukin-2 (IL-2)-dependent proliferation and IL-2 receptor signal transduction in T lymphocytes through complex mechanisms. Here we report that the basal activity, and IL-2- and phorbol ester-dependent activation of the p70/p85 S6 kinases (referred to collectively as pp70S6k) are inhibited by the glucocorticoid dexamethasone (Dex) in CTLL-20 cells. This Dex-induced inhibition is time- and dose-dependent, appears to be the consequence of pp70S6k dephosphorylation, and requires ongoing transcription. Attempts to establish a link between Dex action and those of known pp70S6k-regulating agents such as phosphatidylinositol 3-kinase, protein kinase A-stimulating agents, calyculin A-inhibited protein phosphatases, and rapamycin have been negative. Additional results with NIH3T3 cells suggest the existence of a T cell-specific blockade of pp70S6k by Dex. Implications are 2-fold: 1) pp70S6k inactivation may account for at least part of the immunosuppressive effects of GC in vivo, and 2) GC inactivation of pp70S6k is exerted through a novel, distinct mechanism that does not appear to be linked to any other known pp70S6k regulatory process.
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PMID:Inhibition of p70/p85 S6 kinase activities in T cells by dexamethasone. 888 45

We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. In contrast to IRerbV-->E, the insulin receptor content and its tyrosine phosphorylation were significantly decreased in IRwt cells chronically stimulated (>24 h) with insulin. With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. These data suggest that there are multiple levels of postreceptor desensitization to insulin action. These are used somewhat differently in these two different models, probably due in part to the difference in receptor down-regulation.
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PMID:Different pathways of postreceptor desensitization following chronic insulin treatment and in cells overexpressing constitutively active insulin receptors. 891 Apr 37

Transcription-modulating drugs achieve their therapeutic effects through the modulation of gene transcription. To understand how selectivity is achieved, four groups of such drugs - including immunosuppressants, estrogen analogs, the antidiabetic thiazolidinediones, and the anti-inflammatory salicylates - will be discussed. The immunosuppressants cyclosporin A and FK506, when complexed with immunophilins, inactivate the protein phosphatase calcineurin, resulting in the inhibition of interleukin-2 gene activation. Another immunosuppressant, rapamycin, binds to the same immunophilin as FK506 but inactivates a protein kinase p70(s6k). Estrogen analogs tamoxifen and rolaxifene antagonize one estrogen receptor transactivation function (AF-2) and agonize another (AF-1). They modulate expression of a wide variety of genes, including transforming growth factor-alpha, insulin-like growth factor-1, and transforming growth factor-beta3, which are important for breast and endometrial cancer proliferation and bone maintenance respectively. The antidiabetic drugs thiazolidinediones bind and activate peroxisome proliferator-activated receptor gamma and suppress insulin resistance mediated by tumor necrosis factor-alpha. Salicylates inhibit transcription factor NFkappaB, which is important for immune and inflammatory responses. Continuing understanding of molecular mechanisms of such drugs not only helps to identify better drugs for these targets but should also provide an insight into developing future transcription-modulating drugs with better selectivity and reduced toxicity.
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PMID:Transcription-modulating drugs: mechanism and selectivity. 893 43

The eukaryotic initiation factor 4E (eIF-4E)-binding proteins PHAS-I and PHAS-II were found to have overlapping but different patterns of expression in tissues. Both PHAS proteins were expressed in 3T3-L1 adipocytes, in which insulin stimulated their phosphorylation, promoted dissociation of PHAS.eIF-4E complexes, and decreased the ability of both to bind exogenous eIF-4E. The effects of insulin were attenuated by rapamycin and wortmannin, two agents that block activation of p70(S6K). Unlike PHAS-I, PHAS-II was readily phosphorylated by cAMP-dependent protein kinase in vitro; however, the effects of insulin on both PHAS proteins were attenuated by agents that increase intracellular cAMP, by cAMP derivatives, and by phosphodiesterase inhibitors. These agents also markedly inhibited the activation of p70(S6K). In summary, our results indicate that PHAS-I and -II are controlled by the mammalian target of rapamycin and p70(S6K) signaling pathway and that in 3T3-L1 adipocytes this pathway is inhibited by increased cAMP.
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PMID:Control of the translational regulators PHAS-I and PHAS-II by insulin and cAMP in 3T3-L1 adipocytes. 893 71

We investigated whether or not epidermal growth factor (EGF) and cAMP-elevating agents induce the proliferation of adult rat hepatocytes during the early (4 h after adding EGF) and late phases (21 h after adding EGF) of primary cultures. Adult rat hepatocytes did not significantly proliferate after culture with 20 ng/ml EGF for 4 h at a density of 1 X 10(5) cells/cm2. In contrast, when the density was decreased by about one-third to 3.3 X 10(4) cells/cm2, the number of nuclei increased about 1.2-fold after culture with 10-20 ng/ml EGF for 4 h. Under these culture conditions, DNA synthesis began within 2-4 h of exposure to 20 ng/ml of EGF, although at the high cell density, DNA was not synthesized during this period. The beta-adrenoceptor agonists, metaproterenol and isoproterenol, and other cAMP-elevating agents, such as glucagon, forskolin, and dibutyryl cAMP, potentiated both hepatocyte DNA synthesis and proliferation about 1.4-fold when cultured in combination with 20 ng/ml EGF. The stimulatory effects of metaproterenol and other cAMP-elevating agents were specifically blocked by the cAMP-dependent protein kinase inhibitor, H-89 (10(-7) M). The effect of EGF was almost completely suppressed by genistein (5 X 10(-6) M) and rapamycin (10 ng/ml), but it was unaffected by wortmannin (10(-7) M). These results demonstrate that mature rat hepatocytes can proliferate very rapidly in low-density cultures with EGF, the effects of which were potentiated by beta-adrenoceptor agonists and cAMP-elevating agents. In addition, the activation of receptor tyrosine kinase and p70 ribosomal protein S6 kinase may be involved in EGF-induced hepatocyte DNA synthesis and proliferation.
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PMID:Density-dependent proliferation of adult rat hepatocytes in primary culture induced by epidermal growth factor is potentiated by cAMP-elevating agents. 914 82


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