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)

In herpes simplex virus 1-infected cells, the first set of genes to be expressed (alpha genes) is induced by the alpha gene trans-inducing factor (alpha TIF), a virion structural protein. The cis-acting site in the 5' untranscribed domain of alpha genes was previously reported to be the sequence 5'-GYATGNTAATGARATTCYTTGNGGG noncoding (where Y is a pyrimidine, R is a purine, N is any base), which binds a host protein designated alpha H1 (also termed the octamer binding protein, OTF-1, Oct-1, etc.) and which, together with this and possibly other proteins, forms complexes with alpha TIF. To determine the role of the various components of this cis-acting site and of other sequences shared by the alpha genes, we constructed 17 mutants spanning 110 nucleotides of the promoter domain of the alpha 27 gene and made a series of chimeric genes. Each chimeric gene embodying one set of these mutations was inserted into the viral genome and measurements were made of (i) accumulated mRNA under conditions in which only alpha genes were expressed and (ii) the capacity of the mutated sequence to form complexes containing alpha TIF and alpha H1 proteins. We report that (i) transversions in the "TAAT" sequence abolished both complex formation and induction of the chimeric alpha gene, (ii) mutations in the octamer binding site sequence upstream from TAAT or of the downstream GARAT abolished alpha TIF complex formation and also reduced alpha mRNA accumulation, (iii) mutations in a "CAAT" box also reduced expression of mRNA without affecting the formation of DNA-protein complexes containing alpha TIF, and (iv) mutations in sequences immediately downstream from TAATGARAT and in a pair of GA-rich elements reduced alpha mRNA expression whereas mutations between these elements had no effect on the accumulation of the mRNA. The results are consistent with the conclusion that both the alpha H1 octamer binding site ATGNTAAT and the GARAT sequence play a significant role in the induction of alpha genes. For optimal gene expression, however, additional elements downstream from the GARAT sequence and in other regions of the alpha promoter must be present.
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PMID:Mutational analysis of the promoter region of the alpha 27 gene of herpes simplex virus 1 within the context of the viral genome. 216 72

In order to better understand the role of transcription in cellular processing of damage in specific DNA sequences, we have used an in vitro differentiation system to modulate the activity of the MYC gene. When human HL60 promyelocytic cells differentiate in vitro, the transcriptional activity of the MYC gene is down-regulated. We have shown that in the expressed MYC gene, 56% of UV-induced cyclobutane pyrimidine dimers (CPDs) are removed within 18 h and the transcribed strand is selectively repaired. However, late in differentiation, when the MYC gene is maximally down-regulated, only 15% of the CPDs are removed within the same period. During early differentiation, the MYC gene is regulated by a block to transcription elongation at the 5' end of the first intron. Our results reveal no significant difference in the rate of CPD removal between the restriction fragments upstream and downstream of this elongation block. Furthermore, both strands of each fragment exhibit similar repair characteristics. In contrast, the constitutively expressed FMS gene exhibits proficient removal of CPD in both the differentiated and undifferentiated cells. Furthermore, the repair appears to be more proficient at the 5' end (exon 1) than in the 3' end of the gene about 35 kilobases downstream from exon 1. Since efficient repair of the active FMS gene is maintained in the differentiated cells the loss of repair competence seen in MYC is more likely associated with its reduced transcriptional activity than with a decrease in the overall repair capacity of the terminally differentiated cells.
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PMID:DNA repair in the MYC and FMS proto-oncogenes in ultraviolet light-irradiated human HL60 promyelocytic cells during differentiation. 752 33

Current cancer chemotherapy treatments generally act by affecting rapidly growing malignant cells. Unfortunately, they are relatively nonspecific and thus have a tendency to affect other rapidly growing normal cells in a deleterious manner. Triplex-forming oligodeoxyribonucleotides (TFOs) promise to be a new class of sequence-specific DNA-binding drugs which will target malignancies at the transcriptional level. The formation of an intermolecular triplex (triple helix) has been shown to block the binding of transcription factors and repress transcription in genes such as c-myc and that encoding the epidermal growth factor receptor. The rat neu oncogene promoter contain promoter-enhancer elements which are purine/pyrimidine rich. These enhancer elements are amenable to targeting by TFOs. the human counterpart of rat neu, HER2, is often found to be amplified or overexpressed in a variety of malignancies, such as those of the breast, lungs, ovary, colon and stomach. TFOs may proved to be the basis of effective chemotherapy drugs for these cancers. TFO binding at the "GTG" element (5'GGTGGGGGGG) and at the 'GA' element (5'GGAGGAGGAGGG) has been characterized by gel mobility shift analysis and DNase 1 footprinting. Binding has been shown to occur at a Kd as low as 10(-8) M and has been shown to be sequence specific.
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PMID:Triplex formation at the rat neu oncogene promoter. 795 74

Two frog egg lectins [Rana catesbeiana lectin (SBL-C) and Rana japonica lectin] preferentially agglutinate a large variety of human and animal tumor cells but not blood cells, lymphocytes, or fibroblasts. These lectins belong to the superfamily of pyrimidine base-specific RNases. The two lectins bound to a heparin-Sepharose column and were eluted from the column by an increase of NaCl molarity. Both their tumor cell-agglutinating activity and RNase activity were inhibited by heparin, and also by polyamines, such as spermine. Both lectins inhibited P388 leukemia cell proliferation. The inhibitory activity of SBL-C was blocked by addition of heparin. SBL-C inhibited protein synthesis by P388 cells, but RNase A did not. No lectin-induced antiproliferative effect was observed after sialidase treatment of cells. The antiproliferative activity of SBL-C was also inhibited by ammonium chloride treatment. These results suggest that internalization of the lectins by lectin receptor (sialoglycoconjugate)-mediated endocytosis is followed by cell death due to inhibition of protein synthesis. Administration of SBL-C i.p. delayed time to death in mice receiving i.p. transplants of Sarcoma 180 and Mep II cells.
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PMID:Inhibition of cell proliferation by Rana catesbeiana and Rana japonica lectins belonging to the ribonuclease superfamily. 831 82

A 28-base phosphodiester triple helix-forming oligonucleotide, mostly G and A containing, targeted to a polypurine tract interrupted by a purine-pyrimidine inversion, situated upstream from the TATA box of the promoter of the human HER2 gene, was conceived by computer modeling. The "energetically best choice" was oligo 28(C), which formed the triple helix in vitro, as proved by gel retardation and Fourier transform infrared spectroscopy. When administered as a complex with lipofectin, fluorescence confocal microscopy and electrophoresis confirmed the delivery and persistence of this unprotected oligonucleotide inside MCF7 (breast cancer) cells. At a concentration of 2 microM, the oligonucleotide reduced within 6 h the HER2 mRNA level to 42% (Northern blot) but did not interfere with the transcription of a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. During the first day of administration at 0.22 microM, it lowered to 59% the HER2 protein in treated, as compared to nontreated, cells (ELISA). The effect was sequence specific when compared to that of five different negative controls, and it was target selective when compared to the expression of a related, nontargeted protein, the epidermal growth factor receptor. By day 2, the inhibitory effect was overcome by replenishment reactions.
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PMID:Temporary ex vivo inhibition of the expression of the human oncogene HER2 (NEU) by a triple helix-forming oligonucleotide. 856 64

We have devised and evaluated a stable-isotopic method for measuring DNA synthesis rates. The probe is [1-13C]-glycine that is incorporated into purines via de novo biosynthesis. The human hepatoma cell line HEP G2 was grown in medium containing [1-13C]glycine, the cells were harvested at various times, and the DNA was extracted. Following hydrolysis to the nucleosides, a reversed-phase HPLC separation was used to provide separate peaks for deoxythymidine (dT), deoxyadenosine (dA), and deoxyguanosine (dG). The HPLC effluent was continuously fed into a chemical reaction interface and an isotope ratio mass spectrometer (HPLC/CRI/IRMS). The isotope ratio of the CO2 produced in the CRI was used to monitor for enrichment. The cells were grown continuously for 5 days in labeled medium and also in a 1-day pulse labeling experiment where the washout of label was observed for the subsequent 9 days. As predicted from the role of glycine in de novo purine biosynthesis, the isotope ratio of the pyrimidine dT did not change. However, for the two purines, dA and dG, the characteristic log growth behavior of the cells was observed in their 13C/12C ratios and good agreement in the doubling time was obtained for each type of experiment. Parallel experiments that measured the HEP G2 doubling time in culture using tritiated thymidine incorporation and direct cell counts were carried out compare to our new method with established ones. We believe that the use of [1-13C]-glycine and the HPLC/CRI/IRMS is a highly sensitive and selective approach that forms the basis of a method that can measure DNA synthesis rates using a nonradioactive, nontoxic tracer.
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PMID:Measuring DNA synthesis rates with [1-13C]glycine. 959 74

Vascular endothelial growth factor (VEGF) has been implicated in the pathological induction of new blood vessel growth in a variety of proliferative disorders. Using the SELEX process (systematic evolution of ligands by exponential enrichment), we have isolated 2'-F-pyrimidine RNA oligonucleotide ligands (aptamers) to human VEGF165. Representative aptamers from three distinct sequence families were truncated to the minimal sequence capable of high affinity binding to VEGF (23-29 nucleotides) and were further modified by replacement of 2'-O-methyl for 2'-OH at all ribopurine positions where the substitution was tolerated. Equilibrium dissociation constants for the interaction of VEGF with the truncated, 2'-O-methyl-modified aptamers range between 49 and 130 pM. These aptamers bind equally well to murine VEGF164, do not bind to VEGF121 or the smaller isoform of placenta growth factor (PlGF129), and show reduced, but significant affinity for the VEGF165/PlGF129 heterodimer. Cysteine 137 in the exon 7-encoded domain of VEGF165 forms a photo-inducible cross-link to a single uridine residue in each of the three aptamers. The aptamers potently inhibit the binding of VEGF to the human VEGF receptors, KDR and Flt-1, expressed by transfected porcine aortic endothelial cells. Furthermore, one of the aptamers is able to significantly reduce intradermal VEGF-induced vascular permeability in vivo.
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PMID:2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. 968 13

A role for endogenous histamine and histamine receptor subtypes in mediating the inhibition of eating induced by intragastric (i.g.) hypertonic NaCl was examined in adult male Sprague-Dawley rats surgically equipped with a chronic gastric catheter. The i.g. infusion of 2 mL 900 or 1,800 mOsm/kg of NaCl inhibited: 1) ingestion of pellets in rats eating after 24-h food deprivation; and 2) ingestion of cookies in rats eating without prior deprivation. The H1 receptor antagonists dexbrompheniramine (DXB; 1 mg/kg) and pyrilamine (PYR; 4 mg/kg) did not attenuate the inhibitory effects of i.g. 900 or 1,800 mOsm/kg of NaCl for rats eating pellets and for rats eating cookies. The H2 antagonists cimetidine (CIM; 16 mg/kg) and metiamide (MET; 16 mg/kg) attenuated the inhibitory effects of i.g. 1,800 mOsm/kg of NaCl upon ingestion of cookies, but intracerebroventricular (i.c.v.) infusion (through a chronic indwelling cannula) of 100 microg of CIM did not mimic this effect of intraperitoneal (i.p.) CIM. The i.p. CIM failed to attenuate the inhibition of eating cookies produced by i.p. octapeptide of cholecystokinin (CCK-8; 3 microg/kg). The H3 antagonist thioperamide (TH; 10 mg/kg i.p.) and the H3 agonist R-alpha-methylhistamine (RAM; 3 mg/kg i.p.) did not alter the inhibitory effect of i.g. 1,800 mOsm/kg of NaCl for rats eating cookies. Combined treatments of systemic DXB plus CIM, and DXB plus CIM plus thioperamide (TH) did not reverse the inhibitory effects of i.g. 1,800 mOsm/kg of NaCl upon ingestion of cookies. Finally, i.p. DXB, but not CIM, attenuated the ability of i.g. 900 mOsm/kg of NaCl to increase water intake; conversely, i.p. CIM, but not DXB, attenuated the ability of i.g. 900 mOsm/kg of NaCl to inhibit eating of cookies. These findings demonstrate a double dissociation of effects upon ingestive behavior: H1, but not H2, antagonism attenuates the effect of i.g. hypertonic NaCl on water intake, whereas H2, but not H1, antagonism attenuates the inhibition of eating produced by i.g. hypertonic NaCl. These results demonstrate that different subtypes of peripheral and/or central histamine receptors contribute to different behavioral consequences of postprandial gastrointestinal osmotic loads in rats.
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PMID:H2 histaminergic control of inhibition of eating induced by intragastric NaCl in rats. 981 72

Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range.
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PMID:Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones. 1009 Jul 85

In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the G(q) protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway.
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PMID:5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways. 1068 5


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