Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
J Cell Physiol ; 227(11): 3613-20, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22307729

RESUMEN

Gadd45 proteins function as stress sensors in response to various physiological and environmental stressors, interacting with other cellular proteins implicated in cellular stress responses, including p38 and JNK. This study shows that mice lacking either Gadd45a or Gadd45b are defective in the recruitment of granulocytes and macrophages to the intra-peritoneal cavity following intra-peritoneal administration of the bacterial cell wall pathogen-associated molecular pattern lipopolysaccharide (LPS). Bone marrow derived granulocytes and macrophages lacking either Gadd45a or Gadd45b are shown to be impaired in their chemotactic response to LPS, as well as other inflammatory stimuli such as N-formyl-methionine-leucine-phenylalanine and IL-8. Evidence was obtained also implicating Gadd45a and Gadd45b in other myeloid innate immune functions, including reactive oxygen species production, phagocytosis, and adhesion. Gadd45a and Gadd45b activation of p38 kinase was implicated in the response of granulocytes to LPS mediated chemotaxis, whereas Gadd45a and Gadd45b curtailment of JNK activation was linked to chemotaxis of macrophages in response to LPS. Collectively, these data highlight a novel role for both Gadd45a and Gadd45b in myeloid innate immune functions by differential modulation of p38 and JNK signaling in granulocytes compared to macrophages.


Asunto(s)
Antígenos de Diferenciación , Proteínas de Ciclo Celular , Granulocitos , Inmunidad Innata , Macrófagos , Proteínas Nucleares , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Proteínas de Ciclo Celular/metabolismo , Quimiotaxis , Granulocitos/citología , Granulocitos/inmunología , Granulocitos/metabolismo , Inflamación/genética , Inflamación/inmunología , Interleucina-8/metabolismo , Lipopolisacáridos/administración & dosificación , MAP Quinasa Quinasa 4/antagonistas & inhibidores , MAP Quinasa Quinasa 4/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Proteínas Nucleares/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
2.
Gene ; 405(1-2): 65-78, 2007 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17949927

RESUMEN

HIV-1 transcription is essential for the virus replication cycle. HIV-1 Tat is a viral transactivator that strongly stimulates the processivity of RNA polymerase II (RNAPII) via recruitment of the cyclin T1/CDK9 positive transcription elongation factor, which phosphorylates the C-terminal domain (CTD) of RNAPII. Consistently, HIV-1 replication in transformed cells is very sensitive to direct CDK9 inhibition. Thus, CDK9 could be a potential target for anti-HIV-1 therapy. A clearer understanding of the requirements for CDK9 activity in primary human T cells is needed to assess whether the CDK9-dependent step in HIV-1 transcription can be targeted clinically. We have investigated the effects of limiting CDK9 activity with recombinant lentiviruses expressing a dominant-negative form of CDK9 (HA-dnCDK9) in peripheral blood lymphocytes (PBLs) and other cells. Our results show that direct inhibition of CDK9 potently inhibits HIV-1 replication in single-round infection assays with little to undetectable effects on RNAPII transcription, RNA synthesis, proliferation and viability. In PBLs purified from multiple donors, direct inhibition of CDK9 activity blocks HIV-1 replication/transcription but does not prevent T-cell activation, as determined via measurement of cell surface and cell cycle entry and progression markers, and DNA synthesis. We have also compared the effects of HA-dnCDK9 to flavopiridol (FVP), a general CDK inhibitor that potently inhibits CDK9. In contrast to HA-dnCDK9, FVP interferes with key cellular processes at concentrations that inhibit HIV-1 replication with potency similar to HA-dnCDK9. In particular, FVP inhibits several T-cell activation markers and DNA synthesis in primary PBLs at the minimal concentrations required to inhibit HIV-1 replication. Our results imply that small pharmacological compounds targeting CDK9 with enhanced selectivity could be developed into effective anti-HIV-1 therapeutic drugs.


Asunto(s)
Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , VIH-1/fisiología , Activación de Linfocitos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Linfocitos T/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Línea Celular , Citometría de Flujo , VIH-1/genética , Humanos , Linfocitos T/enzimología , Transcripción Genética
3.
J Immunol ; 175(10): 6402-11, 2005 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-16272292

RESUMEN

Stimulation of primary human T lymphocytes results in up-regulation of cyclin T1 expression, which correlates with phosphorylation of the C-terminal domain of RNA polymerase II (RNAP II). Up-regulation of cyclin T1 and concomitant stabilization of cyclin-dependent kinase 9 (CDK9) may facilitate productive replication of HIV in activated T cells. We report that treatment of PBLs with two mitogens, PHA and PMA, results in accumulation of cyclin T1 via distinct mechanisms. PHA induces accumulation of cyclin T1 mRNA and protein, which results from cyclin T1 mRNA stabilization, without significant change in cyclin T1 promoter activity. Cyclin T1 mRNA stabilization requires the activation of both calcineurin and JNK because inhibition of either precludes cyclin T1 accumulation. In contrast, PMA induces cyclin T1 protein up-regulation by stabilizing cyclin T1 protein, apparently independently of the proteasome and without accumulation of cyclin T1 mRNA. This process is dependent on Ca2+-independent protein kinase C activity but does not require ERK1/2 activation. We also found that PHA and anti-CD3 Abs induce the expression of both the cyclin/CDK complexes involved in RNAP II C-terminal domain phosphorylation and the G1-S cyclins controlling cell cycle progression. In contrast, PMA alone is a poor inducer of the expression of G1-S cyclins but often as potent as PHA in inducing RNAP II cyclin/CDK complexes. These findings suggest coordination in the expression and activation of RNAP II kinases by pathways that independently stimulate gene expression but are insufficient to induce S phase entry in primary T cells.


Asunto(s)
Ciclinas/genética , Ciclinas/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Calcineurina/metabolismo , Calcio/metabolismo , Ciclina T , Humanos , Técnicas In Vitro , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Activación de Linfocitos , Linfocitos/efectos de los fármacos , Sistema de Señalización de MAP Quinasas , Modelos Inmunológicos , Fitohemaglutininas/farmacología , Regiones Promotoras Genéticas , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Regulación hacia Arriba/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA