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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The halogenated pyrimidine analogue 5-bromo-2-deoxycytidine (BCdR) was infused into BALB/C mice bearing EMT-6 tumors via either the intravenous or intra-arterial route. Hepatic dehalogenation of the drug was blocked by 5-diazouracil (DAZU) in order to ascertain its relative importance in the degradation of intravenously administered analogues. Increased radiosensitization was noted with higher intravenous pyrimidine concentrations, but DAZU blockage of dehalogenation had little effect. These studies show that following intravenous infusion, enough BCdR apparently bypasses the hepatic vessels to permit tumor radiosensitization despite dilution of the drug by the systemic circulation.
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PMID:Comparison of intravenous and intra-arterial pyrimidine infusion as a means of radiosensitizing tumors in vivo. 88 82

Primer extension experiments showed that the argR gene, encoding the arginine repressor in Salmonella typhimurium, is transcribed from a single promoter that is negatively regulated by arginine. A repressor overproducing strain was constructed and the repressor was purified to homogeneity. Gel filtration, sedimentation and cross-linking studies established that the native repressor is a hexamer of identical 17,000 Mr subunits. Gel retardation experiments indicate that the apparent dissociation constant for repressor/carAB operator is 6 x 10(-12) M. These experiments showed that arginine is essential for binding of the repressor to the DNA and that pyrimidine nucleotides have no significant effect on this binding. These results indicate that the effect of pyrimidines on expression of the arginine sensitive "downstream" carAB promoter is not directly mediated by the arginine repressor. These experiments also suggest that a single hexamer binds to the carAB operator, which carries two previously defined "ARG box" sequences that characterize operators for arg genes. Gel retardation experiments with DNA fragments carrying the individual ARG boxes showed that both boxes are required for effective binding of the hexameric repressor to the operator, indicating that the ARG boxes comprise a single binding site for the repressor. Analysis of the potential secondary structure of the arginine repressor does not reveal any of the recognizable structural motifs common to a number of DNA-binding proteins. A combination of DNase I, premethylation interference, depurination and hydroxyl radical footprinting techniques were employed to characterize the interactions of the repressor with the carAB operator, with the results suggesting that the repressor predominantly interacts with A.T residues in this region. Comparative DNA sequence analysis of the known arginine operators of enteric bacteria further indicates that the specificity of interaction may be based more on the precise distance between two defined A.T-rich regions rather than on the specific nucleotide sequence.
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PMID:Characterization of the arginine repressor from Salmonella typhimurium and its interactions with the carAB operator. 158 85

5-Chlorodeoxycytidine (CldC), coadministered with modulators of pyrimidine metabolism, is an effective radiosensitizer of murine tumors. Past studies that utilized RIF-1 tumors in C3H mice and Lewis lung carcinoma (LLC) in BDF1 mice have been extended with an emphasis on using multiple cycles of drug administration followed by irradiation of LLC and the use of two additional tumor models. Four of seven cures of BDF1 mice bearing LLC were obtained with three doses of 20 Gy irradiation, in which the first and third dose were preceded by a "Standard Protocol" that includes N-(phosphonacetyl)-L-aspartic acid (PALA), 5-fluorodeoxycytidine (FdC), tetrahydrouridine, and the radiosensitizer, 5-chlorodeoxycytidine. No cures were obtained in groups of mice receiving radiation alone or drugs alone, and there were no "no takes" in untreated control groups (six mice/group). Extensive tumor inhibition, exceeding that obtained with drugs or radiation alone, was obtained with two cycles of drugs and radiation combined when a dimethybenzanthracene-induced mammary adenocarcinoma was used in BALB/c mice. With the EMT-6 tumor in BALB/c mice, doses of 10 and 20 Gy were administered 9 and 16 days after tumor implantation, each preceded with the Standard Protocol; this resulted in a tumor growth delay of 24 days. No tumor growth delay occurred with drugs or radiation alone. The omission of PALA, FdC or CldC from the Standard Protocol resulted in loss of tumor control, which was obtained with the complete protocol. The fact that 5-chlorodeoxycytidine is an effective radiosensitizer in four rodent tumor systems is compelling evidence that it has potential as a radiosensitizer of human tumors, especially in view of its tumor selectivity and its resistance to catabolism when used with modulators of its metabolism, and in view of the high levels of the key enzymes in human tumors, which can convert 5-chlorodeoxycytidine to 5-chlorodeoxyuridine triphosphate, the proximate radiosensitizer.
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PMID:5-chlorodeoxycytidine, a radiosensitizer effective against RIF-1 and Lewis lung carcinoma, is also effective against a DMBA-induced mammary adenocarcinoma and the EMT-6 tumor in BALB/c mice. 173 88

The carAB operon, encoding carbamoylphosphate synthetase (CPSase; EC 6.3.5.5) is transcribed from two tandem promoters. The upstream promoter (P1) is controlled by pyrimidines and the downstream promoter (P2) is controlled by arginine. We have isolated a new type of constitutive mutation (carP) that specifically affects the control of the pyrimidine-sensitive promoter but does not appear to influence other genes of the pyrimidine pathway. The carP mutation acts in trans and is dominant, which suggests that the carP product is an activator of car transcription. The downstream promoter P2, which is repressed by arginine, overlaps two operator modules characteristic of the arginine regulon. We have isolated two operator-constitutive mutations that specifically affect P2; both map in the upstream ARG box at a strongly conserved position.
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PMID:carP, a novel gene regulating the transcription of the carbamoylphosphate synthetase operon of Escherichia coli. 306 18

Thermolabile (TL) phenol sulfotransferase (PST) catalyzes the sulfate conjugation of phenolic monoamines such as dopamine. The level of activity of TL PST in at least one human tissue, the blood platelet, is controlled by a genetic polymorphism. We previously cloned and expressed a cDNA for human liver TL PST and localized its gene, STM, to human chromosome 16p11.2, a region of the chromosome to which the Batten disease gene is also localized. A cDNA for human brain TL PST with an identical open reading frame (ORF) has also been cloned. We have now isolated the human TL PST gene, STM, and have characterized its structural organization as an additional step toward understanding molecular mechanisms involved in the regulation of levels of TL PST activity in human tissue. STM consists of ten exons and nine introns, with a total length of approximately 8.4 kb. Exons range from 88-499 bp in length, while introns vary from 89-1855 bp. Many of the exon-intron splice junctions in STM are located at positions identical to those of splice junctions in the human dehydroepiandrosterone (DHEA) ST gene, STD, and the rat phenol or aryl ST gene. The first two STM exons are represented in the 5'-UTR of a longer TL PST cDNA expressed in both brain and liver, while exon III is represented in a shorter cDNA 5'-UTR expressed in both tissues. These observations suggest alternative transcription initiation and/or alternative splicing as explanations for the existence of TL PST mRNA species with two different 5'-UTRs. 5'-Flanking region(s) of STM contained neither canonical TATA nor CCAAT elements, but they did contain pyrimidine-rich stretches. Northern blot analyses showed that an mRNA species approximately 1.4 kb in length was expressed in human liver, kidney, lung, small intestine, spleen and leukocyte. Molecular cloning and structural characterization of STM will make it possible to study molecular genetic mechanisms involved in the regulation of TL PST activity in human tissue.
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PMID:Human thermolabile phenol sulfotransferase gene (STM): molecular cloning and structural characterization. 769 37

Previously we had characterized the t(1;7)(p34;q34) translocation from HSB-2. This translocation fused the beta T-cell receptor gene (TCRB) constant region and transcriptional enhancer with the type I transcription unit of the LCK gene on the derivative 1 [der(1)] chromosome. The type II promoter was translocated to the der(7) chromosome. Regarding the mechanism of the t(1;7) in HSB-2, we identified an alternating purine-pyrimidine tract (G-T)17 at the 1p34/LCK breakpoint. Additionally, sequence analysis of both breakpoint junctions provided data that implicate the V(D)J recombinase in formation of the t(1;7). A heptamer-nonamer recognition sequence with a 12-bp spacer was found in the immediate vicinity of the 1p34/LCK breakpoint and, thus, chromosomal breakage at 1p34 may be explained as resulting from recombinase activity. Because phosphorylation of Tyr-505 in vivo regulates the tyrosine kinase activity of p56lck we amplified a region from LCK exon 12 that contains the codon for Tyr-505 and showed no mutation of this codon in HSB-2 DNA and, therefore, p56lck in HSB-2 is not activated by mutation of Tyr-505. We have analyzed LCK gene expression in HSB-2 and SUP-T12 cell lines. RNase protection analysis identified almost exclusively type I transcripts in HSB-2. An independent t(1;7) in SUP-T12 also resulted in the juxtaposition of LCK to TCRB. The breakpoint in SUP-T12 occurred 2 kb 5' of the type II promoter, leaving an intact LCK gene on the der(1) chromosome. RNase protection analysis identified both type I and type II LCK transcripts in a 3:1 ratio in SUP-T12. Factors other than proximity to the TCRB enhancer must affect promoter utilization in this cell line.
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PMID:Molecular analysis of the T-cell acute lymphoblastic leukemia-associated t(1;7)(p34;q34) that fuses LCK and TCRB. 804 39

Mutations in arg-13 result in slow growth in minimal medium and can suppress mutations in carbamyl phosphate synthase-aspartate carbamyl transferase within the pyrimidine pathway; the exact biochemical function of the gene product is unknown. To understand the role of arg-13 in arginine metabolism, cosmids rescuing growth in arg-13 mutants were cloned and mapped to the position of arg-13 on LG IR. Northern analysis showed the arg-13 message to contain approximately 2100 nt, although a 1.4-kb genomic fragment truncated at the 5' and 3' ends of the gene encodes a shortened transcript that can rescue arg-13 function. Expression of mRNA arising from the mutant arg-13 gene is induced by arginine starvation, although wild type (arg-13+) is not derepressed in minimal medium. The sequence of the arg-13 gene shows ARG-13 to be a member of the mitochondrial carrier superfamily with three repeats of a approximately 100-amino acid domain, six putative membrane spanning regions, and three copies of the mitochondrial carrier consensus pattern. This information plus available and new nutritional data are consistent with the hypothesis that arg-13 encodes a mitochondrial basic amino acid carrier whose existence was predicted based upon previous physiological, nutritional and biochemical data.
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PMID:Isolation and analysis of the arg-13 gene of Neurospora crassa. 880 90

Leflunomide is an immunosuppressive drug capable of inhibiting T and B cell responses in vivo. A number of studies demonstrate that leflunomide functions both as a pyrimidine synthesis inhibitor and as a tyrosine kinase inhibitor. We previously reported that leflunomide inhibits LPS-stimulated B cell proliferation, cell cycle progression, and IgM secretion. This inhibition can be reversed by the addition of exogenous uridine, suggesting that leflunomide functions as a pyrimidine synthesis inhibitor in B cells. We report here that while the addition of uridine restored proliferation and IgM secretion to leflunomide-treated LPS-stimulated B cells, as determined by metabolic labeling and immunoprecipitation, it did not completely restore secretion of IgG Ab. We hypothesized that leflunomide inhibits LPS-induced IgG secretion by inhibiting tyrosine kinase activity required for isotype switch. We tested this hypothesis in a well-defined model of isotype switch, LPS plus IL-4 induction of IgG1. Leflunomide inhibited IgG1 secretion in this model in a dose-dependent manner. The signal transduction pathway utilized by IL-4 to induce IgG1 involves tyrosine phosphorylation of the IL-4 receptor, JAK1, JAK3, and STAT6 proteins induced by IL-4 binding to the IL-4R. Leflunomide diminished the tyrosine phosphorylation of JAK3 and STAT6 in the absence or presence of uridine. In gel mobility shift studies, STAT6 binding to the STAT6 DNA binding site in the IgG1 promoter decreased in the presence of leflunomide or leflunomide plus uridine. Taken together, these data suggest that leflunomide acts as a tyrosine kinase inhibitor to block IgG1 production.
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PMID:Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. 946 13

Urokinase-type plasminogen activator (uPA) binds to cells via a specific glycosylphosphatidylinositol-anchored receptor. Although occupancy of the uPA receptor (uPAR) has been shown to alter cellular function and to induce gene expression, the signaling mechanism has not been characterized. Urokinase induced an increase in the tyrosine phosphorylation of multiple proteins in bovine aortic endothelial cells. In contrast, low molecular weight uPA did not induce this response. Analysis by immunoblotting demonstrated tyrosine phosphorylation of focal adhesion kinase (FAK), the focal adhesion-associated proteins paxillin and p130(cas), and mitogen-activated protein kinase (MAPK) following the occupancy of the uPAR by uPA. Treatment of cells with phosphatidylinositol-specific phospholipase C, which cleaves glycosylphosphatidylinositol-linked proteins from the cell surface, blocked the uPA-induced tyrosine phosphorylation of FAK, indicating the requirement of an intact uPAR on the cell surface. The uPA-induced activation of MAPK was completely inhibited by genistein, but not by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3, 4-d]pyrimidine, a specific inhibitor of Src family kinases. Thus, this study demonstrates a novel role for the uPAR in endothelial cell signal transduction that involves the activation of FAK and MAPK, which are mediated by the receptor-binding domain of uPA. This may have important implications for the mechanism through which uPA influences cell migration and differentiation.
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PMID:The urokinase-type plasminogen activator receptor mediates tyrosine phosphorylation of focal adhesion proteins and activation of mitogen-activated protein kinase in cultured endothelial cells. 966 Jul 90

G protein-coupled receptors (GPCRs) initiate Ras-dependent activation of the Erk 1/2 mitogen-activated protein kinase cascade by stimulating recruitment of Ras guanine nucleotide exchange factors to the plasma membrane. Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds upon which the GPCR-induced Ras activation complex may assemble. Using specific inhibitors of focal adhesion complex assembly and receptor tyrosine kinase activation, we have determined the relative contribution of each to activation of the Erk 1/2 cascade following stimulation of endogenous GPCRs in three different cell types. The tetrapeptide RGDS, which inhibits integrin dimerization, and cytochalasin D, which depolymerizes the actin cytoskeleton, disrupt the assembly of focal adhesions. In PC12 rat pheochromocytoma cells, both agents block lysophosphatidic acid (LPA)- and bradykinin-stimulated Erk 1/2 phosphorylation, suggesting that intact focal adhesion complexes are required for GPCR-induced mitogen-activated protein kinase activation in these cells. In Rat 1 fibroblasts, Erk 1/2 activation via LPA and thrombin receptors is completely insensitive to both agents. Conversely, the epidermal growth factor receptor-specific tyrphostin AG1478 inhibits GPCR-mediated Erk 1/2 activation in Rat 1 cells but has no effect in PC12 cells. In HEK-293 human embryonic kidney cells, LPA and thrombin receptor-mediated Erk 1/2 activation is partially sensitive to both the RGDS peptide and tyrphostin AG1478, suggesting that both focal adhesion and receptor tyrosine kinase scaffolds are employed in these cells. The dependence of GPCR-mediated Erk 1/2 activation on intact focal adhesions correlates with expression of the calcium-regulated focal adhesion kinase, Pyk2. In all three cell types, GPCR-stimulated Erk 1/2 activation is significantly inhibited by the Src kinase inhibitors, herbimycin A and 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo-D-3,4-pyrimidine (PP1), suggesting that Src family nonreceptor tyrosine kinases represent a point of convergence for signals originating from either scaffold.
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PMID:Pleiotropic coupling of G protein-coupled receptors to the mitogen-activated protein kinase cascade. Role of focal adhesions and receptor tyrosine kinases. 1031 9


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