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)

Rapamycin, which forms a complex with FK506-binding protein and FK506-binding protein-rapamycin-associated protein, induces immunosuppression through an as yet undefined pathway. Our previous studies demonstrated that rapamycin inactivates p7Os6k, which results in the inhibition of translation of ribosomal proteins. Here, we analyzed the mechanism of inactivation of p70s6k by rapamycin using site-directed mutagenesis of the phosphate acceptor site. We introduced a point mutation at Thr229 in the catalytic subdomain VIII of p7Os6k because Thr229 of p7Os6k corresponds to the phosphorylation site of mitogen-activated protein kinases by mitogen-activated protein kinase kinase and to the autophosphorylation site of protein kinase A whose phosphorylation is required for its full activation. Thr229 of rat p70s6k was substituted by either a neutral amino acid Ala (T229A) or by an acidic amino acid Glu (T229E). T229A-P70s6k, expressed in COS cells, migrated faster in SDS-polyacrylamide gels than wild-type p70s6k, and this mutation completely ablated the catalytic activity of the kinase. In contrast, T229E-p70s6k migrated more slowly in SDS-polyacrylamide gels, but demonstrated partial kinase activity (approximately 20% compared with the wild type). These data indicate that the negative charge at Thr229 which is normally achieved by phosphorylation of the residue, is important for the catalytic function of p70s6k. Further, the residual activity of T229E-p70s6k was not affected by rapamycin, implying that rapamycin-induced inactivation of p70s6k may be caused by dephosphorylation or impaired phosphorylation of Thr229.
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PMID:p70 S6 kinase sensitivity to rapamycin is eliminated by amino acid substitution of Thr229. 875 14

This study was designed to evaluate the role of phosphatidylinositol (PI3) kinase, p70 S6 kinase (p70S6K), and mitogen-activated protein (MAP) kinase in the regulation of muscle protein metabolism by insulin and insulin-like growth factor I (IGF-I). Wortmannin and LY294002 (inhibitors of P13 kinase) both abolished the stimulation of protein synthesis by insulin or IGF-I in epitrochlearis muscle incubated in vitro. LY294002 also totally reversed the antiproteolytic action of these hormones. Although p70S6K activation by insulin and IGF-I may be mediated by PI3 kinase in epitrochlearis muscle, the specific inhibition of this kinase by rapamycin caused only partial (25%) inhibition of the stimulation of protein synthesis by these two hormones. Rapamycin had no effect on proteolysis. Finally, insulin or IGF-I did not stimulate MAP kinase activity at any of the times tested (2-25 min), suggesting that this protein kinase was not directly involved in the regulation of muscle protein metabolism. These observations provide evidence that PI3 kinase and p70S6K, but not MAP kinase, play a role in the regulation of muscle protein turnover by insulin or IGF-I.
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PMID:Phosphatidylinositol 3-kinase and p70 s6 kinase participate in the regulation of protein turnover in skeletal muscle by insulin and insulin-like growth factor I. 882 61

Insulin stimulated protein kinase B alpha (PKB alpha) more than 10-fold and decreased glycogen synthase kinase-3 (GSK3) activity by 50 +/- 10% in skeletal muscle and adipocytes. Rapamycin did not prevent the activation of PKB, inhibition of GSK3 or stimulation of glycogen synthase up to 5 min. Thus rapamycin-insensitive pathways mediate the acute effect of insulin on glycogen synthase in the major insulin-responsive tissues. The small and very transient effects of EGF on phosphatidylinositol (3,4,5)P3 PKB alpha and GSK3 in adipocytes, compared to the strong and sustained effects of insulin, explains why EGF does not stimulate glucose uptake or glycogen synthesis in adipocytes.
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PMID:Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. 910 20

Insulin action on both cytoplasmic and nuclear processes is dependent on activation of p70 S6 kinase (p70S6K). In CHO cells expressing human insulin receptors, Western blotting revealed the presence of p70S6K in the cell nucleus at a level of about 32% of that in the cytoplasm. Following insulin treatment, there was a retardation in mobility nuclear p70S6K in SDS-PAGE indicative of a change in phosphorylation of the enzyme, but no change in the amount of enzyme. Stimulation was maximal after 10 min of insulin treatment and decreased gradually at 30 min. There was also a rapid doubling of nuclear p70S6K activity in immunocomplex assays followed by a return to baseline by 30 min. Simultaneously, insulin stimulated cytoplasmic p70S6K by almost 10-fold at 10 min, and activity remained high up to 30 min. Tetradecanoylphorbol acetate (TPA) and fetal calf serum also stimulated nuclear p70S6K as judged by gel mobility shift. TPA also promoted a decrease in cytosolic p70S6K and an increase in nuclear enzyme suggestive of translocation of the enzyme. Rapamycin, a selective inhibitor of p70S6K, and the casein kinase II inhibitor DRB blocked insulin-stimulated nuclear and cytosolic p70S6K. Thus, nuclear p70S6K is regulated by insulin, serum and TPA. The insulin effect is downstream of rapamycin and DRB-sensitive targets and occurs without translocation of the enzyme.
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PMID:Insulin stimulates p70 S6 kinase in the nucleus of cells. 917 75

Rapamycin is a microbial macrolide which belongs to a family of immunosuppressive drugs that suppress the immune system by blocking stages of signal transduction in T lymphocytes. In Saccharomyces cerevisiae cells, as in T lymphocytes, rapamycin inhibits growth and cells become arrested at the G1 stage of the cell cycle. Rapamycin is also an effective antifungal agent, affecting the growth of yeast and filamentous fungi. Unexpectedly, we observed that rapamycin has no apparent effect on the vegetative growth of Schizosaccharomyces pombe. Instead, the drug becomes effective only when cells experience starvation. Under such conditions, homothallic wild-type cells will normally mate and undergo sporulation. In the presence of rapamycin, this sexual development process is strongly inhibited and cells adopt an alternative physiological option and enter stationary phase. Rapamycin strongly inhibits sexual development of haploid cells prior to the stage of sexual conjugation. In contrast, the drug has only a slight inhibitory effect on the sporulation of diploid cells. A genetic approach was applied to identify the signal transduction pathway that is inhibited by rapamycin. The results indicate that either rapamycin did not suppress the derepression of sexual development of strains in which adenylate cyclase was deleted or the cyclic AMP-dependent protein kinase encoded by pka1 was mutated. Nor did rapamycin inhibit the unscheduled meiosis observed in pat1-114 mutants. Overexpression of ras1+, an essential gene for sexual development, did not rescue the sterility of rapamycin-treated cells. However, expression of the activated allele, ras1Val17, antagonized the effect of rapamycin and restored the ability of the cells to respond to mating signals in the presence of the drug. We discuss possible mechanisms for the inhibitory effect of rapamycin on sexual development in S. pombe.
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PMID:Rapamycin specifically interferes with the developmental response of fission yeast to starvation. 933 79

In the marine mollusk Aplysia californica, serotonin initiates three phases of translational regulation: an initial decrease in translation, followed by a transient increase in protein synthesis, both of which are independent of transcription, followed by a later increase in protein synthesis that is dependent on transcription. These increases in protein synthesis may underlie translation-dependent changes in synaptic plasticity. We have characterized the second messenger pathways that underlie these changes in the pleural ganglia of Aplysia. Activation of protein kinase C was both necessary and sufficient for the initial decrease in translation. Protein kinase C, cyclic AMP-dependent protein kinase, and a tyrosine kinase were all required for the second phase, a transient increase in protein synthesis. The late increase in protein synthesis required both protein kinase A and spaced applications of serotonin. Rapamycin, a specific inhibitor of a downstream translational regulator, blocked the transient increase in protein synthesis (second phase), suggesting that this drug may be useful in determining the specific physiological consequences of this translational regulation. Indeed, we used rapamycin to demonstrate that one type of intermediate form of synaptic plasticity induced by serotonin did not require the rapamycin-sensitive increase in translation.
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PMID:Biochemical pathways by which serotonin regulates translation in the nervous system of Aplysia. 945 51

Normal adult rat chromaffin cells show a robust proliferative response in vitro to nerve growth factor (NGF) and other mitogens. In contrast, PC12 rat pheochromocytoma cells proliferate in the absence of exogenous mitogens and undergo neuronal differentiation in response to NGF. We demonstrate in this work that the antiproliferative drug rapamycin suppresses normal chromaffin cell proliferation. This effect is blocked by FK 506, indicating that it occurs via interaction of rapamycin with its intracellular binding protein, FKBP. Rapamycin must be added within 2 days of mitogen stimulation in order to be fully effective. PC12 cells are refractory to the antiproliferative effect of rapamycin, although rapamycin does exert its expected inhibitory effect in PC12 cells on both basal and NGF-stimulated activation of one of its biochemical targets, the 70-kDa S6 protein kinase (p70S6K). The discordant findings suggest that a proliferative signal normally requiring activation of p70S6K either is unnecessary in PC12 cells or is provided by a downstream or cross-communicating pathway. They also suggest that p70S6K does not participate in the morphological responses of PC12 cells to NGF. Determining the basis for rapamycin resistance in PC12 cells might help to identify signaling abnormalities involved in the pathogenesis of pheochromocytoma.
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PMID:Discordant effects of rapamycin on proliferation and p70S6 kinase phosphorylation in normal and neoplastic rat chromaffin cells. 1002 77

Regulation of translation of mRNAs coding for specific proteins plays an important role in controlling cell growth, differentiation, and transformation. Two proteins have been implicated in the regulation of specific mRNA translation: eukaryotic initiation factor eIF4E and ribosomal protein S6. Increased phosphorylation of eIF4E as well as its overexpression are associated with stimulation of translation of mRNAs with highly structured 5'-untranslated regions. Similarly, phosphorylation of S6 results in preferential translation of mRNAs containing an oligopyrimidine tract at the 5'-end of the message. In the present study, leucine stimulated phosphorylation of the eIF4E-binding protein, 4E-BP1, in L6 myoblasts, resulting in dissociation of eIF4E from the inactive eIF4E.4E-BP1 complex. The increased availability of eIF4E was associated with a 1.6-fold elevation in ornithine decarboxylase relative to global protein synthesis. Leucine also stimulated phosphorylation of the ribosomal protein S6 kinase, p70(S6k), resulting in increased phosphorylation of S6. Hyperphosphorylation of S6 was associated with a 4-fold increase in synthesis of elongation factor eEF1A. Rapamycin, an inhibitor of the protein kinase mTOR, prevented all of the leucine-induced effects. Thus, leucine acting through an mTOR-dependent pathway stimulates the translation of specific mRNAs both by increasing the availability of eIF4E and by stimulating phosphorylation of S6.
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PMID:Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. 1020 76

Nitric oxide (NO) regulates the expression of p21(Waf1/Cip1) in several cell types. The present study examined the role of both the extracellular signal-regulated kinase (ERK) and p70 S6 kinase (p70(S6k)) in the NO-induced increase in p21 expression that occurred in adventitial fibroblasts during the cell cycle. Both ERK and p70(S6k) were phosphorylated in response to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and the activation was rapid, transient, and preceded increased p21 expresion under defined conditions where serum was present. Addition of a selective inhibitor of ERK phosphorylation (PD98059) prevented the subsequent phosphorylation of p70(S6k) and the increase in p21 protein. Both cGMP and cAMP activated both ERK and p70(S6k), whereas only selective inhibitors of protein kinase G prevented the activation of the kinases by SNAP. A complex between ERK and p70(S6k) was documented by immunoprecipitation procedures. Rapamycin blocked p70(S6k) phosphorylation induced by NO and also inhibited p53 phosphorylation and p21 expression whereas PD98059 only prevented the NO-induced increase in p21 protein without influencing either p53 activation or p21 mRNA expression. The studies show a unique relationship between NO, ERK, and p70(S6k) and also provide evidence for a novel role of p70(S6k) in the activation of p53.
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PMID:Nitric oxide increases p21(Waf1/Cip1) expression by a cGMP-dependent pathway that includes activation of extracellular signal-regulated kinase and p70(S6k). 1075 54

Ultraviolet radiation induces signal transduction at both early (<6 h) and late (>6 h) times after exposure. The inflammatory and immunosuppressive cytokine tumor necrosis factor alpha is induced at late times, and is induced by ultraviolet-induced DNA damage, as defects in DNA repair increase, and enhanced photoproduct repair reduces, tumor necrosis factor alpha expression. Here we show that late tumor necrosis factor alpha gene expression is sensitive to rapamycin, implicating FKBP12-rapamycin-associated protein, a member of the DNA protein kinase family, as a signal transducer of ultraviolet-induced DNA damage. FKBP12-rapamycin-associated protein was localized in the nucleus of keratinocytes and its level was increased following ultraviolet irradiation. Immuno- precipitated FKBP12-rapamycin-associated protein was stimulated by ultraviolet-irradiated DNA to phosphorylate p53 in vitro, and in vivo rapamycin reduced ultraviolet induction of p53 by 20%. Rapamycin further inhibited the ultraviolet-induced phosphorylation of the FKBP12-rapamycin-associated protein downstream target kinase p70S6K. In mice, topical application of rapamycin before ultraviolet exposure protected against suppression of the contact hypersensitivity that is a hallmark of ultraviolet-induced cytokine gene expression. These results demonstrate that the FKBP12-rapamycin-associated DNA protein kinase transduces the signal of ultraviolet-induced DNA damage into production of immunosuppressive cytokines at late times after ultraviolet irradiation.
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PMID:FRAP DNA-dependent protein kinase mediates a late signal transduced from ultraviolet-induced DNA damage. 1077 84


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