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1.
Nat Genet ; 29(2): 201-5, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11586302

RESUMEN

A comprehensive gene-based map of a genome is a powerful tool for genetic studies and is especially useful for the positional cloning and positional candidate approaches. The availability of gene maps for multiple organisms provides the foundation for detailed conserved-orthology maps showing the correspondence between conserved genomic segments. These maps make it possible to use cross-species information in gene hunts and shed light on the evolutionary forces that shape the genome. Here we report a radiation hybrid map of mouse genes, a combined project of the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, the Medical Research Council UK Mouse Genome Centre, and the National Center for Biotechnology Information. The map contains 11,109 genes, screened against the T31 RH panel and positioned relative to a reference map containing 2,280 mouse genetic markers. It includes 3,658 genes homologous to the human genome sequence and provides a framework for overlaying the human genome sequence to the mouse and for sequencing the mouse genome.


Asunto(s)
Mapeo Cromosómico , Genoma , Células Híbridas/efectos de la radiación , Animales , Etiquetas de Secuencia Expresada , Ratones
2.
Mol Cell Biol ; 20(24): 9423-33, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11094092

RESUMEN

Higher-order chromatin has been implicated in epigenetic gene control and in the functional organization of chromosomes. We have recently discovered mouse (Suv39h1) and human (SUV39H1) histone H3 lysine 9-selective methyltransferases (Suv39h HMTases) and shown that they modulate chromatin dynamics in somatic cells. We describe here the isolation, chromosomal assignment, and characterization of a second murine gene, Suv39h2. Like Suv39h1, Suv39h2 encodes an H3 HMTase that shares 59% identity with Suv39h1 but which differs by the presence of a highly basic N terminus. Using fluorescent in situ hybridization and haplotype analysis, the Suv39h2 locus was mapped to the subcentromeric region of mouse chromosome 2, whereas the Suv39h1 locus resides at the tip of the mouse X chromosome. Notably, although both Suv39h loci display overlapping expression profiles during mouse embryogenesis, Suv39h2 transcripts remain specifically expressed in adult testes. Immunolocalization of Suv39h2 protein during spermatogenesis indicates enriched distribution at the heterochromatin from the leptotene to the round spermatid stage. Moreover, Suv39h2 specifically accumulates with chromatin of the sex chromosomes (XY body) which undergo transcriptional silencing during the first meiotic prophase. These data are consistent with redundant enzymatic roles for Suv39h1 and Suv39h2 during mouse development and suggest an additional function of the Suv39h2 HMTase in organizing meiotic heterochromatin that may even impart an epigenetic imprint to the male germ line.


Asunto(s)
Cromatina/genética , N-Metiltransferasa de Histona-Lisina , Metiltransferasas/genética , Metiltransferasas/metabolismo , Fosfoproteínas/genética , Testículo/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células Cultivadas , Cromatina/metabolismo , Mapeo Cromosómico , Clonación Molecular , Embrión de Mamíferos/metabolismo , Fibroblastos , Expresión Génica , Células Germinativas/metabolismo , Células HeLa , Histona Metiltransferasas , Humanos , Immunoblotting , Hibridación Fluorescente in Situ , Masculino , Metiltransferasas/química , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Datos de Secuencia Molecular , Fosfoproteínas/metabolismo , Filogenia , Proteína Metiltransferasas , ARN/metabolismo , Cromosomas Sexuales/metabolismo , Testículo/anatomía & histología , Testículo/química
3.
Nat Genet ; 22(4): 388-93, 1999 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10431246

RESUMEN

A physical map of the mouse genome is an essential tool for both positional cloning and genomic sequencing in this key model system for biomedical research. Indeed, the construction of a mouse physical map with markers spaced at an average interval of 300 kb is one of the stated goals of the Human Genome Project. Here we report the results of a project at the Whitehead Institute/MIT Center for Genome Research to construct such a physical map of the mouse. We built the map by screening sequenced-tagged sites (STSs) against a large-insert yeast artificial chromosome (YAC) library and then integrating the STS-content information with a dense genetic map. The integrated map shows the location of 9,787 loci, providing landmarks with an average spacing of approximately 300 kb and affording YAC coverage of approximately 92% of the mouse genome. We also report the results of a project at the MRC UK Mouse Genome Centre targeted at chromosome X. The project produced a YAC-based map containing 619 loci (with 121 loci in common with the Whitehead map and 498 additional loci), providing especially dense coverage of this sex chromosome. The YAC-based physical map directly facilitates positional cloning of mouse mutations by providing ready access to most of the genome. More generally, use of this map in addition to a newly constructed radiation hybrid (RH) map provides a comprehensive framework for mouse genomic studies.


Asunto(s)
Cromosomas Artificiales de Levadura , Genoma , Ratones/genética , Mapeo Físico de Cromosoma , Animales , Mapeo Cromosómico , Mapeo Contig , Marcadores Genéticos , Modelos Genéticos
5.
Eur Respir J ; 7(11): 1966-72, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7875266

RESUMEN

Collagen deposition and myofibroblast proliferation beneath the epithelial basement membrane in patients with asthma is now increasingly recognized, although the molecular pathogenesis remains obscure. We have evaluated messenger ribonucleic acid (mRNA) expression of the profibrotic cytokine, platelet-derived growth factor-beta (PDGF-beta), in alveolar macrophages obtained following fibreoptic bronchoscopy and bronchoalveolar lavage in patients with asthma. Three subject groups were studied: 1) asthmatics using regular inhaled glucocorticoid medication (ASTST, n = 9), 2) asthmatics using intermittent inhaled beta 2-agonist therapy only (ASTBR, n = 10); 3) nonasthmatic control volunteers (n = 10). Alveolar macrophage mRNA was extracted and PDGF-beta mRNA quantified by reverse-transcriptase polymerase chain reaction (PCR) (RT-PCR) and expressed as the ratio to that of a control gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). There were no significant differences in PDGF-beta mRNA expression between the groups, or between all asthmatic (n = 19) and control subjects. Furthermore, there was no correlation between alveolar macrophage PDGF-beta mRNA expression and airway spirometry, or duration of glucocorticoid usage or dose. Thus, in contrast to other fibrotic lung diseases, we found little evidence of enhanced expression of PDGF-beta mRNA in alveolar macrophages in clinically stable bronchial asthma.


Asunto(s)
Asma/metabolismo , Macrófagos Alveolares/metabolismo , Factor de Crecimiento Derivado de Plaquetas/genética , Adulto , Aerosoles , Albuterol/uso terapéutico , Asma/tratamiento farmacológico , Beclometasona/uso terapéutico , Northern Blotting , Broncodilatadores/uso terapéutico , Budesonida , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Reacción en Cadena de la Polimerasa , Pregnenodionas/uso terapéutico , ARN Mensajero/metabolismo , Fumar , Terbutalina/uso terapéutico
6.
Clin Exp Immunol ; 94(1): 43-50, 1993 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8403516

RESUMEN

Macrophage production of PDGF-B is believed to be important in the pathogenesis of diseases where chronic lung inflammation develops into fibrosis. Since tuberculosis is characterized by chronic inflammation and tissue fibrosis, we asked if lymphokines from lymphocytes stimulated by the Mycobacterium tuberculosis antigen PPD, contained factors capable of increasing human alveolar macrophage PDGF-B mRNA. Supernatants from both phytohaemagglutinin (PHA)- and purified protein derivative (PPD)-stimulated lymphocytes, when added to macrophages, induced an increase in the mRNA of PDGF-B, but not transforming growth factor-beta (TGF-beta). When lymphocytes from contacts of patients with tuberculosis, patients with tuberculosis, and normal subjects were compared following PPD stimulation, the lymphocytes from the contacts had the greatest proliferation response, the greatest production of interferon-gamma (IFN-gamma), and their lymphokines induced the greatest increase in PDGF-B mRNA in macrophages. Recombinant human IFN-gamma reproduced this ability of lymphokines to increase macrophage PDGF-B mRNA. Finally, the increase in macrophage PDGF-B mRNA following incubation with supernatants from PPD-stimulated lymphocytes was shown to be due to IFN-gamma, when the increase in macrophage PDGF-B mRNA was prevented by addition of anti-human IFN-gamma antibody to the lymphocyte supernatant. This study indicated that antigen-stimulated lymphocytes released IFN-gamma, which in turn resulted in an increase in PDGF-B mRNA in alveolar macrophages. Such a mechanism provides a link between the DTH response and the first stages of a fibrotic reaction, and may offer an explanation for the progression of chronic inflammation to fibrosis, as occurs in the lungs of patients with untreated pulmonary tuberculosis.


Asunto(s)
Interferón gamma/fisiología , Activación de Linfocitos , Macrófagos Alveolares/metabolismo , Factor de Crecimiento Derivado de Plaquetas/genética , ARN Mensajero/análisis , Tuberculina/inmunología , Secuencia de Bases , Concanavalina A/farmacología , Antígenos HLA-DR/genética , Humanos , Linfocitos/inmunología , Datos de Secuencia Molecular , Fitohemaglutininas/farmacología , ARN Mensajero/genética , Regulación hacia Arriba
7.
Mol Pharmacol ; 42(4): 584-9, 1992 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-1331750

RESUMEN

Macrophage production of growth factors for fibroblasts, in particular platelet-derived growth factor B [PDGF(B)] and transforming growth factor-beta (TGF-beta), is thought to be central to the pathogenesis of pulmonary fibrosis. In a search for anti-inflammatory agents that might prevent this process, we asked whether colchicine might modulate the abundance of PDGF(B) and TGF-beta mRNA, as well as the mRNA of early growth response gene 2 (EGR2), in human macrophages. Colchicine caused a dose- and time-dependent increase in PDGF(B), but not TGF-beta or EGR2, mRNA in human macrophages derived from culture of peripheral blood monocytes. Similarly, colchicine caused an increase in PDGF(B) mRNA in human alveolar macrophages obtained from normal volunteers. Colchicine also caused an increase in PDGF(B) protein production by macrophages, as determined by enzyme-linked immunosorbent assay. Interferon-gamma further increased the PDGF(B) mRNA abundance in human alveolar but not monocyte-derived macrophages. The effect of coincubation with dibutyryl-cAMP (dBcAMP) was assessed in an attempt to prevent the colchicine-induced increase in PDGF(B) mRNA. dBcAMP alone resulted in no increase in PDGF(B) mRNA or alteration in TGF-beta mRNA but resulted in a reduction in EGR2 mRNA. When added with colchicine, dBcAMP completely abrogated the colchicine-induced increase in PDGF(B) mRNA but had little effect on TGF-beta mRNA. These data, showing that colchicine increased macrophage PDGF(B) mRNA in human macrophages and that this was prevented by coincubation with dBcAMP, lead us to speculate that colchicine may not be helpful in preventing the contribution of macrophage PDGF(B) gene activation to the pathogenesis of lung fibrosis. However, this effect of colchicine may be prevented by increasing intracellular cAMP in macrophages.


Asunto(s)
Bucladesina/farmacología , Colchicina/farmacología , Macrófagos/fisiología , Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas Proto-Oncogénicas/genética , Expresión Génica/efectos de los fármacos , Antígenos HLA-DR/genética , Humanos , Técnicas In Vitro , Interferón gamma/farmacología , Macrófagos Alveolares/fisiología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-sis , ARN Mensajero/genética , Proteínas Recombinantes , Factor de Crecimiento Transformador beta/genética
8.
Am J Respir Cell Mol Biol ; 7(2): 198-206, 1992 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1497907

RESUMEN

Platelet-derived growth factor (B) (PDGF(B)) from alveolar macrophages is thought to play a central role in orchestrating the fibrotic response. Because corticosteroids are widely used in the treatment of patients with lung fibrosis, we asked whether corticosteroids modulated PDGF(B) gene activation in macrophages. PDGF(B) mRNA in alveolar macrophages obtained from smokers was increased after culture in the presence of dexamethasone (P less than 0.05), interferon-gamma (IFN-gamma) (P less than 0.05), or both in combination (P less than 0.05). Dexamethasone did not alter the abundance of mRNA encoding transforming growth factor-beta (TGF-beta), but did decrease the mRNA of early growth response gene 2 (EGR2). These initial experiments required large numbers of cells and thus were performed on macrophages from smokers. The results were reproduced when PDGF(B) mRNA abundance in macrophages from healthy nonsmoking volunteers was measured by the reverse-transcriptase polymerase chain reaction (RT-PCR). There was an increase in PDGF(B) mRNA in macrophages from nonsmokers after stimulation with dexamethasone alone (P less than 0.05) or in combination with IFN-gamma (P less than 0.05). To provide adequate cell numbers for kinetic and dose-response studies, the in vitro model of phorbol ester (TPA)-induced differentiation of HL60 cells to macrophage-like cells was used. In these cells, dexamethasone caused a 20-fold increase in the abundance of PDGF(B) mRNA, which was concentration and time dependent but not associated with changes in TGF-beta or EGR2 mRNA. This study suggests that in addition to their anti-inflammatory effects, corticosteroids may also increase the abundance of PDGF(B) mRNA.


Asunto(s)
Dexametasona/farmacología , Macrófagos Alveolares/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/genética , Adulto , Secuencia de Bases , Líquido del Lavado Bronquioalveolar , Diferenciación Celular/efectos de los fármacos , Línea Celular , Sondas de ADN , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Interferón gamma/farmacología , Macrófagos Alveolares/citología , Macrófagos Alveolares/metabolismo , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Acetato de Tetradecanoilforbol/farmacología , Transcripción Genética
10.
Lancet ; 1(8634): 352-5, 1989 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-2563508

RESUMEN

Linkage between Alzheimer's disease and markers on the long arm of chromosome 21 was investigated in six families affected by disease of early onset. Linkage was confirmed and the disease locus shown to be centromeric to the locus D21S1/S11 on the long arm of the chromosome. It is argued that the data are consistent with the notion that all patients with Alzheimer's disease of genetic aetiology have a predisposing locus on chromosome 21.


Asunto(s)
Enfermedad de Alzheimer/genética , Aberraciones Cromosómicas/genética , Mapeo Cromosómico , Cromosomas Humanos Par 21 , Adulto , Southern Blotting , Trastornos de los Cromosomas , Femenino , Ligamiento Genético , Humanos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Longitud del Fragmento de Restricción , Recombinación Genética
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