Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aspirin-intolerant asthma (AIA), a distinct clinical syndrome affecting about 10% of adult asthmatics, appears to be unusually dependent on cysteine leukotriene (cys-LT) overproduction by pulmonary eosinophils. The gene coding for leukotriene (LT) C(4) synthase (LTC(4)S), the enzyme controlling cys-LT biosynthesis, exists as two common alleles distinguished by an A to C transversion at a site 444 nucleotides upstream of the translation start. We tested the hypothesis that this single nucleotide polymorphism (SNP) affects binding of transcription factors and influences the transcription rate, predisposing to AIA. Gel shift assay studies revealed that the (-444)C allele, conferring an activator protein-2 binding sequence, is an additional target for a transcription factor of histone H4 consensus. Introduction of the H4TF-2 decoy oligonucleotide into LTC(4)S-positive, differentiated HL-60 cells decreased accumulation of LTC(4) to 68%. Transfection of COS-7 with promoter construct increased expression of beta-galactosidase reporter for the (-444)C variant. The (-444)C allelic frequency was significantly higher in AIA patients (n = 76) as compared with matched aspirin-tolerant asthmatics (n = 110) and healthy controls (n = 75). Patients with AIA had also upregulated LTC(4)S messenger RNA expression in peripheral blood eosinophils. An inhaled provocation test with lysine-aspirin led to an increase in urinary output of LTE(4), which reached statistical significance only in carriers of the (-444)C allele. Our results suggest that a transcription factor, present in dividing and bone marrow resident progenitors of eosinophils, triggers LTC(4)S transcription in carriers of a common (-444)C allele due to binding with the histone H4 promoter element of the gene. Genetic predisposition to cys-LT pathway upregulation, a hallmark of AIA, can be related to overactive expression of the LTC(4)S (-444)C allele.
Am J Respir Cell Mol Biol 2000 Sep
PMID:Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. 1097 Aug 15

Using the oligosphere strategy (V. Avellana-Adalid et al., 1996, J. Neurosci. Res. 45, 558-570), we compared the migratory behavior of oligodendrocyte preprogenitors (OPP) that expressed the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) and of GD3-positive oligodendrocyte progenitors (OP). To study the role of PSA in OPP migration, we used endoneuraminidase-N, which specifically cleaves PSA from NCAM. Kinetic data showed that (i) migration velocity decreased with time and was favored on polyornithine compared to Matrigel; (ii) cells emerging from spheres enriched in PSA-NCAM+ OPP migrated farther than those from spheres enriched in GD3+ OP, their migration being enhanced by the addition of growth factors; (iii) removal of PSA from NCAM moderately reduced OPP migration and induced their differentiation in GD3+ OP and GFAP+ astrocytes; (iv) blocking integrins reduced their migration, suggesting an alternative mechanism of migration. Altogether these data illustrate that motility and differentiation of OPP involve the combinatorial action of PSA-NCAM, molecules of the ECM and their receptors, and growth factors.
Mol Cell Neurosci 2000 Oct
PMID:Oligodendrocyte precursor migration and differentiation: combined effects of PSA residues, growth factors, and substrates. 1108 79

In this article we report the application of the Promolecular Atomic Shell Approximation (Promolecular ASA) to the graphical representation of the density function (DF) of large macromolecular systems. Promolecular ASA DF, constructed from previously computed and fitted atomic densities, provides a fast and practical representation of Molecular IsoDensity Contours (MIDCOs). These representations can be extended to macromolecular systems composed by > 1000 atoms easily and with low computational costs, allowing the visualization of protein DF. The method is at first presented with a small molecule (2,4,6-trinitrophenol), comparing the resulting ASA MIDCOs with direct ab initio contours. For macromolecular tests the Promolecular ASA densities are also applied to the generation of macromolecular density surfaces of two proteins: myoglobin (2541 atoms) and gene V protein (1362 atoms).
J Mol Graph Model 2001
PMID:Application of promolecular ASA densities to graphical representation of density functions of macromolecular systems. 1144 74

FAR-2 is a novel neural member of the Ig superfamily, which is related to F11/F3/contactin and axonin-1/TAG-1. This protein is expressed by subpopulations of Purkinje cells in the chicken cerebellum and FAR-2-positive clusters of these neurons alternate with FAR-2-negative clusters in both tangential dimensions of the cerebellar cortex. Furthermore, FAR-2 is also expressed by one type of Purkinje cell afferents, namely, the climbing fibers, and different subpopulations of these axons show distinct levels of FAR-2 expression. Homology modeling using axonin-1 as a template reveals that the four aminoterminal Ig domains of FAR-2 form a compact U-shaped structure, which is likely to contain functionally important ligand-binding sites. FAR-2 is binding to the Ig superfamily protein NgCAM/L1, but not to the related receptor NrCAM, and it is also interacting with the modular ECM protein tenascin-R. These results suggest that FAR-2 may contribute to the formation of somatotopic maps of cerebellar afferents during the development of the nervous system.
Mol Cell Neurosci 2001 Jul
PMID:The contactin-related protein FAR-2 defines purkinje cell clusters and labels subpopulations of climbing fibers in the developing cerebellum. 1146 Nov 56

Aspirin is unique among clinically used nonsteroidal antiinflammatory drugs in that it irreversibly inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue. We report the synthesis and characterization of a novel acetylating agent, O-acetylsalicylhydroxamic acid (AcSHA), which inhibits PGE2 synthesis in vivo and blocks the cyclooxygenase activity of PGHS in vitro. AcSHA requires the presence of the active-site residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by the inhibitor. Analysis of PGHS inactivation by AcSHA, coupled with the X-ray crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits its effects via acetylation of Ser-529 in the cyclooxygenase active site. The crystal structure reveals an intact inhibitor molecule bound in the enzyme's cyclooxygenase active-site channel, hydrogen bonding with Arg-119 of the enzyme. The structure-activity profile of AcSHA can be rationalized in terms of the crystal structure of the enzyme-ligand complex. AcSHA may prove useful as a lead compound to facilitate the development of new acetylating inhibitors.
Mol Pharmacol 2001 Dec
PMID:O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions. 1172 49

The endocrine actions of follicle stimulating hormone and luteinising hormone on ovarian cells are transduced by locally produced paracrine factors that regulate the formation of extracellular matrix, proteolytic enzymes and protease inhibitors, which continuously remodel the parenchymal environment in which follicles develop. We recently identified connective tissue growth factor (CTGF) as a gene expressed during the predifferentiated stage of granulosa cell development in rat ovary. The CTGF gene encodes a protein that is implicated in the regulation of connective tissue synthesis, mototaxis, angiogenesis and cellular interaction with ECM at various sites in the body. Stimulation of granulosa cells by FSH in vitro and in vivo induces follicular maturation associated with down-regulation of granulosa cell CTGF mRNA expression. The gene remains expressed in cells of the innermost (antrally located) granulosa compartment up to and after the point of ovulation. Based on the inferred biological properties of CTGF protein and the spatiotemporal pattern of CTGF mRNA expression in the ovary, we postulate roles for ovarian CTGF during early stages of follicular development and after ovulation in the formation of the corpus luteum.
Mol Cell Endocrinol 2002 Feb 22
PMID:Connective tissue growth factor in the ovarian paracrine system. 1198 8

In the past few years, a series of molecular-genetic, biochemical, cellular and behavioral studies in fruit flies, sea slugs and mice have confirmed a long-standing notion that long-term memory formation depends on the synthesis of new proteins. Experiments focused on the cAMP-responsive transcription factor, CREB, have established that neural activity-induced regulation of gene transcription promotes a synaptic growth process that strengthens the connections among active neurons. This process constitutes a physical basis for the engram--and CREB is a "molecular switch" to produce the engram. Helicon Therapeutics has been formed to identify drug compounds that enhance memory formation via augmentation of CREB biochemistry. Candidate compounds have been identified from a high throughput cell-based screen and are being evaluated in animal models of memory formation. A gene discovery program also seeks to identify new genes, which function downstream of CREB during memory formation, as a source for new drug discoveries in the future. Together, these drug and gene discovery efforts promise new class of pharmaceutical therapies for the treatment of various forms of cognitive dysfunction.
J Mol Neurosci
PMID:CREB and the discovery of cognitive enhancers. 1221 77

We examined beta1 integrin expression during angiogenesis in the developing mouse CNS. Maturation of blood vessels was accompanied by three main events: (1) marked upregulation of beta1 integrin expression; (2) a switch in beta1 integrin expression, from alpha4 and alpha5 at postnatal day 1 to alpha1 and alpha6 in the adult; and (3) downregulation of fibronectin and upregulation of laminin expression. Thus, blood vessel maturation was associated with a developmental switch, from fibronectin-mediated signaling early in angiogenesis, to laminin-mediated signaling at later stages. To investigate the potential role of alpha4 and alpha5 integrins in angiogenesis, we developed a novel approach to purify endothelial cells from the CNS by selective adhesion to fibronectin. BrdU incorporation showed that fibronectin induced more endothelial cell proliferation than laminin, and antibody-blocking studies revealed that fibronectin mediated its effect via both alpha4 and alpha5 integrins. This work provides the first evidence that there is a developmental switch in the use of beta1 integrins during angiogenesis. Furthermore, it suggests that regulation of beta1 integrin and ECM expression by endothelial cells are important factors influencing vascular development in the CNS.
Mol Cell Neurosci 2002 Aug
PMID:Developmental regulation of beta1 integrins during angiogenesis in the central nervous system. 1221 43

The formation of protrusions along the shaft of neurites might be important in the establishment and refinement of neuronal connections during development. In a search for extracellular signals that affect the formation of microprocesses along neurites we found that the ECM glycoprotein tenascin-R (TN-R) but not other ECM glycoproteins increased the percentage of tectal neurons with actin-rich microprocesses and side branches. Longer actin-based microprocesses were also invaded by microtubuli in their proximal part. The formation of microprocesses by TN-R extending laterally along the neuritic shaft was time- and dose-dependent. In addition to the induction of microprocesses, TN-R increased the size of the growth cone of tectal neurons. A cross-species experiment in combination with blocking antibodies demonstrated that the TN-R-induced effects are mediated by the Ig superfamily member contactin. These observations suggest that TN-R via its neuronal receptor contactin might induce a transition from long-distance growth of tectal interneurons to differentiation, including the formation of microprocesses.
Mol Cell Neurosci 2002 Dec
PMID:Tenascin-R induces actin-rich microprocesses and branches along neurite shafts. 1250 95

Aspirin irreversibly inhibits cyclooxygenase (COX) by acetylating a serine residue in the active site. We synthesized a series of novel acylating agents based on our previously reported acetylating compound, O-acetylsalicylhydroxamic acid. One of these, triacetylsalicylhydroxamic acid (TriAcSHA) was more effective than aspirin and O-acetylsalicylhydroxamic acid in inactivating both COX-1 and COX-2. Preincubation of COX-1 with inhibitor for 5 min yielded IC(50) values of 18 microM for TriAcSHA and 60 microM for acetylsalicylic acid. Inhibition was time-dependent, with complete inhibition within 10 min at a concentration of 50 microM. As with aspirin, mutation of the serine 530 of COX-1 to alanine abolished the activity of the TriAcSHA. Mutation of the alanine 119 to a glutamine markedly reduced the sensitivity to TriAcSHA, suggesting that this residue was necessary for the interaction with the enzyme. TriAcSHA was also more effective than aspirin as an inhibitor of platelet aggregation induced by arachidonic acid. The diacetylated phenylhydroxamates N-methyl-O,O-diacetylsalicylhydroxamic acid, N,O-diacetylbenzohydroxamic acid, and 2-methyl-O,N-diacetylbenzohydroxamic acid showed reduced or absent activity against COX-1. In addition, we synthesized a series of triacylsalicylhydroxamic acids with progressively longer acyl groups (three to six carbons). All of the compounds inhibited COX-1 and demonstrated progressively greater COX-1 selectivity with increasing number of carbons. Hence, salicylhydroxamic acid provides a versatile backbone for the generation of a family of acylating inhibitors of cyclooxygenase.
Mol Pharmacol 2003 Feb
PMID:A novel family of hydroxamate-based acylating inhibitors of cyclooxygenase. 1252 17


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