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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The action of theophylline derivatives (-)-7-2-(2-hydroxy-1-methyl-2-phenyl-ethylamino)-ethyl-theophyl-line (cafedrine) and 7-2-2-(3,4-dihydroxy-phenyl-2-hydroxy-ethylamino)-ethyl-theophylline (theodrenaline) on free fatty acids (FFA) levels in rat blood serum and on cyclic AMP (cAMP) accumulation and FFA mobilization in isolated fat cells has been studied and compared to the action of a noradrenaline plus aminophylline mixture (NAA). A significant in vivo increase of FFA appeared 15 min after NAT and 90 min after NET i.p. administration. NAA was active at both times. Unlike NET, NAT stimulated in vitro FFA mobilization and cAMP accumulation: NAA action was however stronger. NAT-mediated cAMP accumulation, but not that which was NAA-induced, was totally inhibited by timolol. Our results suggest the existence of a beta-adrenergic mechanism for NAT and a tyraminic mechanism for NET. A theophyllinic action dos not seem to apply to either drug.
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PMID:Differences in the lipolytic and cyclic AMP accumulative action of noradrenaline-theophylline and norephedrine-theophylline. 625 57

Recently we have described that the Herpes simplex virus (HSV)-induced thymidine kinase (TK) induces AMP- and ADP-dThd-5'-phosphotransferase activities. We now demonstrate the heterogeneity of the described activities in isoelectric focusing experiments and polyacrylamide gel electrophoresis. A TK--mutant of HSV type 1 fails to induce these activities. The activities of the type 1 enzyme complex was neutralized by an anti-HSV-serum. The TK-enzyme complex expressed in LTK--cells transformed to a TK+-phenotype by sheared HSV-1 DNA was compared with the wild type TK complex in isoelectric focusing experiments. Additionally we demonstrate that the HSV type 1 enzyme complex has thymidylate kinase activity, while the type 2 TK complex did not exhibit thymidylate kinase activity. Feedback regulation mechanisms by dTMP, dTDP and dTTP were investigated using partially purified enzyme preparations of HSV types 1 and 2 infected TK--cells.
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PMID:Analysis of the TK enzyme complex induced by HSV types 1 and 2 by means of isoelectric focusing and polyacrylamide gel electrophoresis. 628 60

To observe the effects of polyoma virus DNA on the expression of the herpes simplex virus (HSV) thymidine kinase (TK) gene early after transfer into TK-deficient mouse cells and the subsequent development of stable TK-positive transformants, we constructed a series of recombinant plasmids containing the herpes simplex virus TK gene joined with various segments of the polyoma virus genome and microinjected them into the nuclei or cytoplasm of LTK-A cells (TK(-), APRT(-)). The frequency of nucleus-injected cells expressing TK after 1 day, measured by autoradiography of cells incubated with [(3)H]thymidine, increased approximately 30-fold when the plasmids contained the polyoma virus origin of replication. The origin includes sequences with homology to the simian virus 40 origin of replication and adjoining sequences, including a recently defined transcription-enhancing sequence. After microinjection of a single origin-containing plasmid molecule per cell, TK expression was detected in approximately 50% of the injected cells. When a larger number of origin-containing plasmid molecules were injected per cell, all cells showed early TK activity. When the entire polyoma virus early region was present, neighboring uninjected cells became TK positive. When plasmids were injected into the cell cytoplasm, approximately 400 times as many molecules per cell were needed to cause early TK activity. The frequency of stable transformation observed 2 weeks after nuclear injection of 10 to 20 polyoma virus origin-containing plasmid molecules per cell was at least 2 orders of magnitude greater than with plasmids containing the TK gene alone. The greatest enhancement of stable TK transformation was obtained with plasmids containing the origin alone, when the maximum frequency of stable transformation was 5%. The addition of the coding regions for the small and medium T antigens or the entire early region significantly decreased TK transformation frequency in a copy-dependent fashion. The timing of stabilization of TK-positive transformation was analyzed by releasing hypoxanthine-aminopterin-thymidine selection pressure at various times after microinjection, culturing the cells in nonselective medium, and assaying for TK activity. Stabilization was found to occur between 3 and 6 days after nuclear injection. Cells injected with a plasmid containing the origin and the early region were examined for expression of the large T antigen with polyoma virus antitumor serum and immunofluorescent staining. The expression of the large T antigen was clearly associated with a cytopathic effect. TK-positive clones observed 2 weeks after injection of the plasmid were uniformly T antigen negative. Cytotoxicity may be the result of plasmid replication and toxic levels of T antigen or TK. In addition, expression of the large T antigen may block stabilization by preventing the integration of origin-containing plasmid molecules.
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PMID:Expression and stabilization of microinjected plasmids containing the herpes simplex virus thymidine kinase gene and polyoma virus DNA in mouse cells. 630 96

After transfection of mouse mammary tumor virus (MMTV) proviral DNA into cultured cells, the DNA is transcribed in a glucocorticoid-sensitive fashion. The large terminal repeat (LTR) region of MMTV is 1,328 nucleotides long and contains the regulatory information necessary for the hormonal response. We have constructed a MMTV LTR-thymidine kinase (tk) chimeric gene and have tested the biological activity of molecules containing various deletions in the LTR after transformation of LTK- APRT- mouse cells. In the TK+ transformants, both a LTR- tk chimeric RNA and an authentic tk RNA are correctly initiated and transcribed. The synthesis of the chimeric RNA as well as that of the tk RNA is hormonally regulated. A plasmid containing 202 nucleotides of LTR DNA 5' to the RNA initiation site is fully sensitive to glucocorticoids; 50 nucleotides still cause a residual inducibility.
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PMID:Subfragments of the large terminal repeat cause glucocorticoid-responsive expression of mouse mammary tumor virus and of an adjacent gene. 630 28

Karyotypes of recessive mutants at the autosomal adenine phosphoribosyltransferase (Aprt) locus in a clone of the near-diploid mouse CAK cell line have been analyzed. The Aprt located on chromosome 8. One copy of chromosome 8 was morphologically abnormal in the parental clone (CAK-B3-Toyr13) from which Aprt- mutants were isolated. Among 22 mutants, there were ten in which one copy of chromosome 8 had been lost. Four of these were monosomic, and in the others duplication of the remaining homolog had occurred. These findings indicate that newly induced recessive mutations in cultured mammalian cells can be expressed as the result of loss of one chromosome carrying a wild-type allele with or without duplication of the homolog carrying the mutant allele. Loss and duplication would not be detected in cell lines lacking morphologically marked chromosomes.
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PMID:Expression of recessive Aprt- mutations in mouse CAK cells resulting from chromosome loss and duplication. 658 43

A consensus cyclic AMP response element (CRE) in the murine prostaglandin synthase-2 (PGS2) promoter is essential for pgs2 gene expression induced by pp60v-src, the v-src oncogene product. In this study, we investigate (i) the transcription factors active at the PGS2 "CRE site" in response to v-src activation and (ii) the signal transduction pathways by which pp60v-src activates these transcription factors. Transient transfection assays with pgs2 promoter/luciferase reporter chimeric genes suggest that c-Jun mediates v-src-induced pgs2 gene expression. Antibody supershift experiments demonstrate that c-Jun can participate in a complex with the pgs2 promoter CRE site. Moreover, in vitro immuno-complex assays demonstrate that pp60v-src expression strongly activates c-Jun N-terminal kinase (JNK1) enzyme activity. Serines 63 and 73, the sites of c-Jun phosphorylation by JNK, are essential for v-src-induced, pgs2 promoter-mediated luciferase expression. Cotransfection studies with plasmids expressing wild-type JNK, dominant-negative JNK, and dominant-negative MEKK-1 confirm that activation of the Ras/MEKK-1/JNK/c-Jun pathway is required for v-src-induced pgs2 gene expression. Overexpression of either wild-type ERK-1 or ERK-2 proteins also potentiate v-src-mediated luciferase expression driven by the pgs2 promoter, and expression of dominant-negative mutants of ERK-1, ERK-2, or Raf-1 attenuate this response. Thus, in response to v-src expression, a Ras/MEKK-1/JNK signal transduction pathway activating c-Jun and a Ras/Raf-1/ERK pathway converge to mediate pgs2 gene expression via the CRE site in the pgs2 promoter.
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PMID:v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. 749 26

The Cl- conductance of a mouse fibroblast cell line (LTK- cells) that was stably transfected with the human CFTR (cystic fibrosis transmembrane conductance regulator) complementary DNA was studied. Single Cl- channel activity was observed only after treatment of the cells with forskolin, the single-channel conductance being 6.2 +/- 0.2 pS with a linear current-voltage relationship. In CFTR+ cells, the whole-cell current at +90 mV increased from 7.3 +/- 2.7 pA/pF (n = 12) to 46.1 +/- 11.2 pA/pF (n = 5) after addition of dibutyryl-cyclic AMP (10(-4) M) to the bath. Increasing the intracellular Cl- concentration to 150 mM activated linear Cl- currents in the absence of cyclic AMP in CFTR+ (n = 42) but not in CFTR- cells (n = 4). Similar Cl- current was also activated by high intracellular I- concentration. These results indicate that the CFTR-induced Cl- conductance in LTK- cells can be activated by either cyclic AMP or high intracellular halide concentrations.
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PMID:Activation of Cl- currents by intracellular chloride in fibroblasts stably expressing the human cystic fibrosis transmembrane conductance regulator. 750 15

Activation of the RET protooncogene tyrosine kinase (tk) by fusion with other genes is a frequent finding in papillary thyroid carcinoma. The tk domain of proto-RET can be fused either with the D10S170 gene generating the RET/PTC1 transforming sequence or with sequences belonging to the gene encoding the regulatory subunit RIA of c-AMP-dependent protein kinase A, thus forming the RET/PTC2 oncogene. We have previously shown that an inversion of chromosome 10, inv(10)(q11.2q21), is responsible for the generation of the RET/PTC1. Here we report that a chromosomal translocation, t(10;17)(q11.2;q23), juxta-poses the tk domain of the RET protooncogene, which resides on chromosome 10, to a 5' portion of the RIA gene on chromosome 17, leading to the formation of the chimeric transforming gene RET/PTC2. The finding of the transforming protein in primary tumor cell extracts supports the conclusion that RET/PTC2 activation plays a role in papillary thyroid tumorigenesis.
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PMID:A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. 751 46

It is well-established that agonist-mediated desensitization of the beta 2-adrenergic receptor (beta 2AR) involves its phosphorylation by protein kinase A (PKA) and the beta AR kinase (beta ARK). The phosphorylated receptor is less efficient at mediating agonist stimulation of adenylyl cyclase activity. The result is an increase in the concentration of agonist required for half-maximal stimulation (EC50) and a reduction in maximal stimulation (Vmax). As less is known about desentization of the human beta 1 AR, we compared the desensitization pattern of human beta 1 AR and beta 2AR stably expressed in two different hamster cell lines: Chinese hamster ovary (CHO), and Chinese hamster fibroblast (CHW). Following agonist treatment, all of the cell lines exhibited an increase in EC50, and a reduction in Vmax was observed in CHO-beta 2 but not beta 1 cells. CHW-beta 1 cells were resistant to acute agonist-mediated reduction in Vmax compared to CHW-beta 2 cells. More prolonged agonist exposure produced a modest reduction in Vmax and this effect was more noticeable when the CHW cells expressed lower levels of beta 1AR. To explore the role of protein kinases in these effects, digitonin-permeabilized CHW cells were loaded either with heparin (a beta ARK inhibitor) or a peptide inhibitor of PKA and exposed to agonist. In both beta 2AR- and beta 1AR-expressing cells, heparin inhibited the reduction in Vmax and the PKA inhibitor blocked the increase in EC50. Finally, exposing CHW cells expressing either subtype to a permeable cyclic AMP derivative caused an increase in EC50 similar to that observed in agonist-treated cells, but without any reduction in maximal activity. Our data suggest that whereas PKA-mediated desensitization is not subtype-specific, human beta 1AR is more resistant to beta ARK-mediated desensitization compared to the human beta 2AR.
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PMID:Differences in desensitization between human beta 1- and beta 2-adrenergic receptors stably expressed in transfected hamster cells. 766 9

Bradykinin activates adenylate cyclase via a pathway that involves the 'up-stream' regulation of phospholipase D (PLD)-catalysed hydrolysis of phosphatidylcholine and activation of protein kinase C (PKC) in airway smooth muscle [Stevens, Pyne, Grady and Pyne (1994) Biochem. J. 297, 233-239]. Coincident signal (Gs alpha and PKC) amplification of the cyclic AMP response can be completely attenuated either by diverting PLD-derived phosphatidate or by inhibiting PKC. In this regard, the coincident signal detector type II adenylate cyclase is expressed as a 110/112 kDa polypeptide in these cells. PKC alpha is not involved in the activation of adenylate cyclase, since a B2-receptor antagonist (NPC567, 10 microM) blocked its bradykinin-stimulated translocation to the membrane and was without effect against both bradykinin-stimulated PLD activity and cyclic AMP formation. Cyclic AMP formation can also be activated by platelet-derived growth factor (PDGF), via a PKC-dependent pathway, although the magnitude of the response is less than that elicited by bradykinin. Nevertheless, these results indicate that multiple receptor types employ PKC to initiate cyclic AMP signals. PDGF (10 ng/ml) elicited the marked sustained activation of extracellular-signal-regulated kinase-2 (ERK-2), whereas bradykinin (1 microM) provoked only modest transient activation of ERK-2. Deoxyadenosine (0.1 mM), a P-site inhibitor of adenylate cyclase, blocked bradykinin-stimulated cyclic AMP formation and converted the activation of ERK-2 into a sustained response. Thus the PKC-stimulated cyclic AMP response can limit the activation of ERK-2 in response to bradykinin. These studies indicate that the integration of distinct signal pathways by adenylate cyclase can determine the kinetics of ERK activation, an enzyme that appears to be important for mitogenic progression.
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PMID:Protein kinase C-dependent cyclic AMP formation in airway smooth muscle: the role of type II adenylate cyclase and the blockade of extracellular-signal-regulated kinase-2 (ERK-2) activation. 799 98


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