RESUMEN
Resistance to chemotherapy hinders the successful treatment of acute lymphoblastic leukemia (ALL). The multi-drug resistance-1 (MDR1/ABCB1) gene encodes P-glycoprotein (P-gp), which plays an important role in chemoresistance; however, its transcriptional regulation remains unclear. We investigated the role of YY1 in the regulation of MDR1 and its relation to ALL outcomes. Analysis of the MDR1 promoter revealed four putative YY1-binding sites, which we analyzed using a reporter system and ChIP analysis. YY1 silencing resulted in the inhibition of MDR1 expression and function. The clinical roles of YY1 and MDR1 expression were evaluated in children with ALL. Expression of both proteins was increased in ALL patients compared to controls. We identified a positive correlation between YY1 and MDR1 expression. High levels of YY1 were associated with decreased overall survival. Our results demonstrated that YY1 regulates the transcription of MDR1. Therefore, YY1 may serve as a useful prognostic and/or therapeutic target.
Asunto(s)
Biomarcadores de Tumor/análisis , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factor de Transcripción YY1/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Proliferación Celular , Niño , Preescolar , Estudios de Cohortes , Etopósido/farmacología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Regiones Promotoras Genéticas , Tasa de Supervivencia , Células Tumorales Cultivadas , Factor de Transcripción YY1/genéticaRESUMEN
Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-ß were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-ß correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-ß expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB.
Asunto(s)
Quimiocina CCL4/metabolismo , Pulmón/microbiología , Tuberculosis Pulmonar/metabolismo , Factor de Transcripción YY1/metabolismo , Animales , Línea Celular , Quimiocina CCL4/genética , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Inmunohistoquímica , Pulmón/inmunología , Masculino , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Interferencia de ARN , Estudios Retrospectivos , Transducción de Señal , Factores de Tiempo , Análisis de Matrices Tisulares , Transcripción Genética , Transfección , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Factor de Transcripción YY1/genéticaRESUMEN
Despite clinical recovery of patients from an episode of acute kidney injury (AKI), progression to chronic kidney disease (CKD) is possible on long-term follow-up. However, mechanisms of this are poorly understood. Here, we determine whether activation of angiotensin-II type 1 receptors during AKI triggers maladaptive mechanisms that lead to CKD. Nine months after AKI, male Wistar rats develop CKD characterized by renal dysfunction, proteinuria, renal hypertrophy, glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis. Renal injury was associated with increased oxidative stress, inflammation, α-smooth muscle actin expression, and activation of transforming growth factor ß; the latter mainly found in epithelial cells. Although administration of losartan prior to the initial ischemic insult did not prevent or reduce AKI severity, it effectively prevented eventual CKD. Three days after AKI, renal dysfunction, tubular structural injury, and elevation of urinary biomarkers were present. While the losartan group had similar early renal injury, renal perfusion was completely restored as early as day 3 postischemia. Further, there was increased vascular endothelial growth factor expression and an early activation of hypoxia-inducible factor 1 α, a transcription factor that regulates expression of many genes that help reduce renal injury. Thus, AT1 receptor antagonism prior to ischemia prevented AKI to CKD transition by improving early renal blood flow recovery, lesser inflammation, and increased hypoxia-inducible factor 1 α activity.