Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Proteínas Portadoras/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Metilación de ADN , Proteínas de Unión al ADN/genética , Epigénesis Genética , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Meduloblastoma/patología , Meduloblastoma/terapia , Proteínas Nucleares/genética , Fenotipo , Pronóstico , Factores de Riesgo , Factores de Transcripción/genéticaAsunto(s)
Producción de Medicamentos sin Interés Comercial/legislación & jurisprudencia , United States Health Resources and Services Administration/legislación & jurisprudencia , Costos de los Medicamentos/legislación & jurisprudencia , Humanos , Honorarios por Prescripción de Medicamentos/legislación & jurisprudencia , Estados UnidosAsunto(s)
Cannabis , Comercio/legislación & jurisprudencia , Control de Medicamentos y Narcóticos/legislación & jurisprudencia , Fumar Marihuana/legislación & jurisprudencia , Preparaciones de Plantas , Colorado , Comercio/economía , Regulación Gubernamental , Humanos , Preparaciones de Plantas/economíaAsunto(s)
Antígenos de Neoplasias/uso terapéutico , Azacitidina/análogos & derivados , Vacunas contra el Cáncer/uso terapéutico , Metilación de ADN/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Proteínas de la Membrana/uso terapéutico , Recurrencia Local de Neoplasia/terapia , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , Antígenos de Neoplasias/inmunología , Azacitidina/uso terapéutico , Vacunas contra el Cáncer/inmunología , Carcinoma Epitelial de Ovario , Terapia Combinada , Metilasas de Modificación del ADN/antagonistas & inhibidores , Metilasas de Modificación del ADN/metabolismo , Decitabina , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de la Membrana/inmunología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/inmunología , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Resultado del TratamientoRESUMEN
The anaphase promoting complex/cyclosome (APC/C) is a multisubunit ubiquitin ligase that acts as a key regulator in the progression through mitosis (when mostly in complex with Cdc20) and as a stabilizer of the G1 phase (when in complex with Cdh1). Cdh1 is an activator of APC/C, and it has previously been reported that it is capable of mediating its own degradation during Go and G1. Herein, we show that the SCF complex (Skp1/Cul1/F-box protein/Roc1) intervenes in the surveillance of Cdh1 cellular abundance in S-phase.
Asunto(s)
Proteínas de Ciclo Celular/química , Complejos de Ubiquitina-Proteína Ligasa/fisiología , Secuencias de Aminoácidos , Ciclosoma-Complejo Promotor de la Anafase , Proteínas Cdh1 , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Doxiciclina/farmacología , Fase G1 , Eliminación de Gen , Genes Dominantes , Células HeLa , Humanos , Immunoblotting , Mitosis , Conformación Proteica , Interferencia de ARN , Fase de Descanso del Ciclo Celular , Fase S , Factores de Tiempo , Transfección , Ubiquitinas/químicaRESUMEN
Ubiquitin-dependent proteolysis ensures that specific protein functions are turned off at the right time, in the right place, and in a unidirectional fashion. The high substrate specificity of the system is determined by a large family of ubiquitin ligases, which competes with the protein kinases to be the largest family of enzymes in mammals. Given the crucial function of the proteolytic machinery, altered degradation of cellular regulators contributes to the unchecked proliferation typical of cancer cells. Here we review the aberrant activity of a variety of ubiquitin ligases in human cancer, hence the prospect of targeting them in cancer therapy.
Asunto(s)
Cisteína Endopeptidasas/metabolismo , Ligasas/metabolismo , Complejos Multienzimáticos/metabolismo , Ubiquitina/metabolismo , Animales , Humanos , Modelos Moleculares , Mutación , Neoplasias/tratamiento farmacológico , Oncogenes/fisiología , Fosforilación , Complejo de la Endopetidasa Proteasomal , Desnaturalización Proteica/fisiología , Proteínas Supresoras de Tumor/fisiologíaRESUMEN
Neuropeptide Y appears to modulate epileptic seizures differentially according to the receptor subtypes involved. In the hippocampus, neuropeptide Y expression and release are enhanced in different models of epileptogenesis. On the contrary, the expression of Y1 receptors is decreased and it has been shown that activation of these receptors has pro-convulsant effects. The aim of our study was to investigate the role of Y1 receptors during hippocampal kindling epileptogenesis using (i) knock-out mice lacking Y1 receptors and (ii) intrahippocampal infusion of Y1 antisense oligodeoxynucleotide in rats. Y1 knock-out mice showed similar susceptibility to seizure induction and presented no difference in kindling development as compared with their control littermates. Conversely, local hippocampal down-regulation of Y1 receptors during the first week of hippocampal kindling, induced by a local infusion of a Y1 antisense oligodeoxynucleotide, significantly increased seizure threshold intensity and decreased afterdischarge duration. A reverse effect was observed during the week following the infusion period, which was confirmed by a significant decrease in the number of hippocampal stimulations necessary to evoke generalized seizures. At the end of this second week, an up-regulation of Y1 receptors was observed in kindled rats infused with the antisense as compared with the mismatch-treated controls. Our results in the rat suggest that the down-regulation of Y1 receptors in the hippocampus participates in the control of the initiation of epileptogenesis. The lack of an effect of the deficiency of Y1 receptors in the control of kindling development in Y1 knock-out mice could be due to compensatory mechanisms.
Asunto(s)
Hipocampo/fisiología , Excitación Neurológica/fisiología , Neuropéptido Y/fisiología , Receptores de Neuropéptido Y/fisiología , Animales , Western Blotting , Regulación hacia Abajo , Ratones , Ratones Noqueados , Oligodesoxirribonucleótidos Antisentido , Ratas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/genética , Factores de TiempoRESUMEN
Chronic intrahippocampal infusion of the neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to delay kindling epileptogenesis in the rat and several lines of evidence suggest that neuropeptide Y could mediate these inhibitory effects. Chronic infusion of BDNF leads to a sustained overexpression of neuropeptide Y in the hippocampus, which follows a time course similar to that of the suppressive effects of BDNF on kindling. In vivo, acute applications of neuropeptide Y or agonists of its receptors exert anticonvulsant properties, especially on seizures of hippocampal origin. In this study, we examined how chronic infusion of this neuropeptide in the hippocampus affected kindling epileptogenesis. A 7-day continuous infusion of neuropeptide Y in the hippocampus delayed the progression of hippocampal kindling in the rat, whereas anti-neuropeptide Y immunoglobulins had an aggravating effect. These results show that neuropeptide Y exerts anti-epileptogenic properties on seizures originating within the hippocampus and lend support to the hypothesis that BDNF delays kindling at least in part through upregulation of this neuropeptide. They also suggest that the seizure-induced upregulation of neuropeptide Y constitutes an endogenous mechanism counteracting excessive hippocampal excitability.