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)

Unipolar depression, alcoholism and suicide have become more common over the past decades. Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci for insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. Since TH and the insulin receptor require phosphorylation by protein kinases, then a defect of the h-ras-oncogene or its products (p21) could disorder both these systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. This could lead not only to a predisposition to depression ('trait markers') but to neurotoxic damage, predisposed by inadequate cytosol Mg2+ levels of hypometabolism. Tyrosine, tryptophan and phenylalanine hydroxylases all require tetrahydrobiopterin (BH4) which allosterically regulates its own activity as well as that of these enzymes. Anything which impairs this cofactor could lead to overt depression in predisposed individuals, and the heterocyclic amines are being increasingly implicated. These substances are derived from fried and broiled meats, azo food dyes, soft drinks and hard candies, but particularly from cigarette and petroleum fumes. The heterocyclic amines can inhibit aromatic-l-amino-acid-decarboxylase (AADC) as well as the hydroxylases reversibly, but BH4 is inhibited noncompetitively. Thus, susceptible individuals (those with inherited defective protein kinase phosphorylation) might be 'tipped over' by chronic exposure to these neurotoxins. The rising incidence of unipolar depression-associated morbidity could be significantly linked to increasing levels of heterocyclic amines in the developed nations.
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PMID:The 'cerebral diabetes' paradigm for unipolar depression. 814 51

CD8+ T cells from naturally infected disease-resistant sooty mangabeys (Cercocebus atys) secrete a soluble factor which inhibits the in vitro replication of the simian immunodeficiency virus (SIV). To gain further insight on the mechanism(s) involved, CD8+ effector T cells and target cells from sooty mangabeys were immortalized and cloned. The target cells were then stably transfected with an SIV-LTR-CAT construct or with the parental CAT plasmid as a control. A quantitative RT-PCR method, providing the necessary sensitivity, was developed to monitor the influence of the cloned CD8+ T cells on the CATmRNA contained in the target cells. It could be demonstrated that a soluble factor was secreted by the cloned CD8+ T cells from sooty mangabeys, which appeared to regulate CATmRNA activity in a dose-dependent and reversible manner. Kinetic experiments showed that the CATmRNA transcriptional activity was initially augmented at 30 min postcoculture and was followed by a marked decrease in transcriptional activity after a few hours. This immediate early response could be mitigated utilizing H7, Calmodulin, or PDTC (a pyrrolidone derivative of dithiocarbamate), suggesting that the pathway was protein kinase-dependent and that the NF-kappa B site may be involved. The inhibitory effect could also be overcome using a protein synthesis inhibitor, suggesting that protein synthesis was needed to negatively regulate CATmRNA activity and hence SIV promoter activity.
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PMID:Biphasic in vitro regulation of retroviral replication by CD8+ cells from nonhuman primates. 815 36

The Raf-1 proto-oncogene product is a highly regulated serine/threonine kinase that functions in signal transduction downstream from growth factor receptors and upstream from nuclear proto-oncogene products. Using a transient cotransfection assay we have found that activated Raf-1 activates expression from the HIV-LTR. Analysis of a series of 5' deletion and point mutations revealed the NF-kappa B motifs as the Raf-responsive element in the HIV-LTR. Moreover, Raf-BXB activated expression from heterologous promoters driven by the HIV NF-kappa B binding sites. In addition to Raf, we show that v-Src, v-H-Ras and v-Mos activate HIV-LTR expression through the NF-kappa B binding sites and v-H-Ras-induced HIV-LTR expression is mediated by Raf-1. These findings may have implications for the involvement of the cellular homologues of these oncogenes in the switch from latent to productive infection by HIV in response to T-cell activation.
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PMID:Oncogene activation of HIV-LTR-driven expression via the NF-kappa B binding sites. 825 80

The type-I regulatory subunit (RI) of the cyclic AMP-dependent protein kinase (PKA) from Chinese hamster ovary (CHO) cells has been cloned and expressed in a strain of BL21(DE3) Escherichia coli lacking adenylate cyclase [BL21(DE3)/delta cya]. RI expressed in this bacterial system free of cyclic AMP is soluble and can reconstitute functional PKA. Recombinant CHO C alpha is predominantly insoluble with some active soluble protein. C beta is entirely insoluble and inactive. Soluble recombinant RI and soluble recombinant C alpha can associate in vitro and be activated by cyclic AMP. Six site-directed mutations of RI were generated to study the interaction of cyclic AMP with RI and RI-C alpha subunit interactions. Four cyclic AMP-binding-site point mutants were generated [W261R (tryptophan to arginine at position 261), a novel mutation in site A; V376G, a novel mutation in site B; G200E (site A), and Y370F (site B), previously described in bovine RI were introduced into the CHO RI for comparison purposes]. Mutants W261R, Y370F, and G200E demonstrated decreased 8-N3-[3H]cyclic AMP binding as well as 5-fold reduced affinity for [3H]cyclic AMP, with threefold increased EC50 values for cyclic AMP activation of kinase activity from reconstituted mutant holoenzymes. The mutation at V376G did not alter cyclic AMP binding or activation by cyclic AMP of mutant holoenzyme. A truncation mutant, G200Stop, which lacks both cyclic AMP-binding sites, did not bind cyclic AMP but can inhibit C alpha subunit activity. A novel mutation outside the cyclic AMP-binding regions of RI (V89A) weakened the interaction with C alpha indicated by a 7-fold lower EC50 for mutant holoenzyme activation by cyclic AMP.
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PMID:Bacterial expression of Chinese hamster regulatory type-I and catalytic subunits of cyclic AMP-dependent protein kinase and mutational analysis of the type-I regulatory subunit. 828 Jan 13

The p34cdc2 protein serine-threonine kinase plays an essential role in the life cycle of fission yeast, being required for both the G1-S and G2-M transitions during mitotic growth, and also for the second meiotic nuclear division. Functional homologues of p34cdc2 (each ca. 60% identical to the fission yeast prototype) have been isolated from organisms as diverse as humans, insects and plants, and there is now considerable evidence supporting the view that fundamental aspects of the cell cycle controls uncovered in fission yeast will prove to be conserved in all eukaryotes. By comparing the amino acid sequences of fission yeast p34cdc2 with its higher eukaryotic counterparts it is possible to identify conserved residues that are likely to be centrally important for p34cdc2 function. Here the effects are described of mutating a number of these conserved residues. Twenty-three new mutant alleles have been constructed and tested. We show that replacing cysteine 67 with tryptophan renders the resulting mutant protein p80cdc25-independent (while neither leucine, isoleucine nor valine has this effect) and that several of the amino acids within the highly conserved PSTAIRE region are not absolutely required for p34cdc2 function. Five acidic amino acids have also been mutated within p34cdc2, which are invariant across the eukaryotic protein kinase family. Acid-to-base mutations at three of these residues resulted in a dominant-negative, cell cycle arrest phenotype while similar mutations at the other two simply abolished p34cdc2 protein function. The results are discussed with reference to the predicted tertiary structure of the p34cdc2 enzyme.
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PMID:Mutational analysis of the fission yeast p34cdc2 protein kinase gene. 843 86

The avian retroviral oncoprotein v-Rel and its cellular homolog c-Rel are members of a family of related site-specific DNA-binding proteins. Towards the carboxy-terminal end of the highly conserved Rel homology (RH) domain in the majority of Rel proteins, there is a consensus recognition sequence for protein kinase A (PK-A). We have investigated the importance of this sequence (Arg-Arg-Pro-Ser) for several functional properties of v-Rel and c-Rel. Disruption of the PK-A sequence by a two amino acid insertion between the arginine and the proline residues completely abolished the ability of v-Rel and c-Rel to bind a kappa B site in vitro. When the phosphorylatable serine in this sequence (Ser-275 in v-Rel, Ser-266 in c-Rel) was replaced by an alanine, DNA binding by v-Rel was not affected, whereas the ability of c-Rel to bind DNA was reduced approximately fourfold by this mutation. Similarly, a serine to tryptophan change greatly reduced the DNA-binding ability of c-Rel, whereas v-Rel was not appreciably affected by this change. When this serine was replaced by an acidic amino acid, DNA binding by v-Rel was reduced approximately twofold and the DNA-binding activity of c-Rel was nearly abolished. Glutaraldehyde cross-linking experiments indicated that mutations at the PK-A recognition site that reduced DNA binding also negatively affected protein oligomerization, which is likely to be responsible for the reduced ability of mutant v-Rel and c-Rel proteins to bind DNA. Domain-swapping experiments showed that structural differences between v-Rel and c-Rel in the central region of the proteins are primarily responsible for the higher sensitivity of c-Rel to a serine to alanine mutation in the PK-A site. One difference between v-Rel and c-Rel, a glutamine to alanine change in v-Rel located three amino acids carboxy-terminal to the PK-A phosphorylatable serine (Ala-278 in v-Rel; Glu-269 in c-Rel), is mainly responsible for the lack of an effect on DNA binding by v-Rel when Ser-275 is replaced by alanine. That is, a v-Rel double mutant (v-275A/278E) showed reduced DNA-binding and transforming abilities as compared with v-Rel and v-275A. Similarly, the mutations in c-Rel that affected DNA binding showed a corresponding effect on the ability of c-Rel proteins to activate transcription in yeast from a reporter gene containing upstream Rel binding sites.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:v-Rel and c-Rel are differentially affected by mutations at a consensus protein kinase recognition sequence. 843 55

Nuclear proteins of the human peripheral blood T lymphocytes that bind to the CREs located within three 21-bp repeat enhancers of the HTLV-I promoter belong to the CREB/CREM family of bZIP transcription factors. It has been shown previously that Tax enhances transactivation of these CREs by direct interactions with the bZIP domain of the transcription factors to stabilize DNA-binding. We show that CREB and CREM bind all three CRE sequences of the HTLV-I promoter which are important determinants in Tax-elicited transactivation as well as PKA-mediated activation of the HTLV-I promoter. Tax and PKA activate transcription from a HTLV-I-LTR CAT reporter plasmid transfected to NIH 3T3 cells, and CREM attenuates the activation. In the context of a GAL4 CREB fusion protein in which the DNA-binding bZIP domain of CREB is replaced by GAL4 binding domain, a single amino acid substitution of serine-133, phosphorylated by PKA and critical for the transactivation function of CREB, attenuates both Tax and PKA-mediated transcriptional responses. These observations suggest that Tax enhances CREB-mediated transactivation of the HTLV-I promoter by a mechanism apart from, and/or in addition to, the reported stabilization of DNA-binding by interaction with the bZIP domain of CREB.
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PMID:Modulation of Tax and PKA-mediated expression of HTLV-I promoter via cAMP response element binding and modulator proteins CREB and CREM. 854 66

The catalytic subunit of protein kinase A increases brain tryptophan hydroxylase activity. The activation is manifested as an increase in Vmax without alterations in the Km for either tetrahydrobiopterin or tryptophan. The activation of tryptophan hydroxylase by protein kinase A is dependent on ATP and an intact kinase and is inhibited specifically by protein kinase A inhibitors. Protein kinase A also catalyzes the phosphorylation of tryptophan hydroxylase. The extent to which tryptophan hydroxylase is phosphorylated by protein kinase A is dependent on the amount of kinase used and is closely related to the degree to which the hydroxylase is activated. These results suggest that a direct relationship exists between phosphorylation and activation of tryptophan hydroxylase by protein kinase A.
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PMID:Phosphorylation and activation of tryptophan hydroxylase by exogenous protein kinase A. 859 57

Recombinant human liver phenylalanine hydroxylase (PAH) expressed in Escherichia coli has been purified to homogeneity. The recombinant enzyme exists in solution as a mixture of 80% tetramers and 20% dimers. A study of the kinetic properties of the enzyme indicates that compared to the recombinant and the native rat liver enzymes, the recombinant human enzyme is in an activated state. This conclusion is supported by the finding that its catalytic activity is only marginally stimulated by incubation with either phenylalanine or lysolecithin. In contrast, the native and the recombinant rat liver enzymes are activated 8- to 25-fold, respectively, when preincubated with phenylalanine or lysolecithin. In the absence of activators, the ratio of the hydroxylase activity in the presence of 6-methyl-5,6,7,8-tetrahydropterin compared to the activity in the presence of (6R)-5,6,7,8-tetrahydrobiopterin (BH4), which is an index of the state of activation of the enzyme, is 4 for the human recombinant PAH compared to a value of 12 for the recombinant rat liver enzyme. Furthermore, the Km for phenylalanine in the presence of BH4 is 0.050 mM, a value that is one-fifth that of the recombinant rat liver enzyme. Covalent modification of the human enzyme by phosphorylation with protein kinase A provides further evidence that the human enzyme is in a substantially activated state. Phosphorylation, which results in the incorporation of 0.6 mol of phosphate/mol of subunit, leads to only a modest activation of 1.5-fold compared to about a 3-fold activation seen after phosphorylation of the native and the recombinant rat liver enzymes. Moreover, the recombinant human liver enzyme is less sensitive than the rat liver enzyme to stimulation by lysolecithin when tryptophan is the substrate. Just as is true for the rat liver enzyme, the apparent Km values for tryptophan and pheylalanine vary with the pterin cofactor employed. The ability of 7-tetrahydrobiopterin (7-BH4) to substitute for the natural cofactor tetrahydrobiopterin has been studied in vitro. The apparent Km for 7-BH4 for the recombinant human enzyme is 0.2 mM and the Km for phenylalanine is 0.05 mM. The hydroxylase reaction is severely inhibited by 7-BH4 in the presence of physiological concentrations of BH4. This inhibition can be overcome by a decrease in the concentration of phenylalanine. The implications of these novel properties of human PAH for phenylalanine homoestasis in man are discussed.
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PMID:Recombinant human phenylalanine hydroxylase: novel regulatory and structural properties. 880 57

In vitro, human B lymphocytes undergo long-term proliferation when activated through CD40, a protein expressed on their cell surface. The nature of CD40-dependent signals in proliferating fresh human Epstein-Barr virus-negative B lymphocytes is currently unknown. In this study, a CD40-dependent B cell culture system was used to examine the role of different signal transduction elements. Protein kinase C (PKC) depletion generated by a long-term phorbol 12 myristate 13-acetate treatment had weak effects on proliferation. Rather, tyrosine phosphorylation was shown to be directly involved in mediating CD40-dependent signals. The use of the protein tyrosine kinase (PTK)-specific inhibitor herbimycin A dramatically decreased cellular proliferation without altering the activity of the human immunodeficiency virus-1 long terminal repeat (HIV-1 LTR), a promoter largely dependent on the binding of nuclear factor kappa B (NF- kappa B). In contrast, the cAMP-dependent protein kinase specific inhibitor H-89 totally inhibited HIV-1 LTR activity at a concentration as low as 100 nM without affecting cellular proliferation. Electrophoretic mobility shift assay (EMSA) and supershift assay using an NF-kappa B binding sequence from the kappa light chain as a probe, revealed that both p65 (RelA) and c-Rel were present in CD40-stimulated B cells. While PKC depletion did not alter the NF-kappa B level, treatment of B lymphocytes with H-89 or herbimycin A provoked a decrease in the NF-kappa B level. These observations establish the importance of different signal transducing pathways leading to CD40 activation of B lymphocytes.
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PMID:Tyrosine kinase and cAMP-dependent protein kinase activities in CD40-activated human B lymphocytes. 889 48


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