Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation.
Blood
; 113(16): 3744-53, 2009 Apr 16.
Article
en En
| MEDLINE
| ID: mdl-19096009
ABSTRACT
Chronic lymphocytic leukemia (CLL) is characterized by cells that exhibit dysfunctional apoptosis. Here, we show that deacetylase inhibition led to the E2F1- and myc-mediated transcriptional activation of the microRNA miR106b in primary CLL cells. Induction of miR106b was associated with a down-regulation in the levels of the E3-ubiquitin ligase Itch. Decreases in Itch protein levels were associated with a reciprocal accumulation of its proapoptotic substrate, TAp73 (p73), and induction of p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein. This event was accompanied by mitochondrial dysfunction, processing of caspase-9, and apoptosis of CLL cells. Ectopic expression of miR106b in CLL cells demonstrated that Itch was a direct target of miR106b such that miR106b-induced decreases in Itch resulted in an accumulation of p73. Thus, our results identify a novel regulatory mechanism wherein microRNA regulate cell survival by mediating the posttranscriptional down-regulation of an ubiquitin ligase, leading to the induction of a proapoptotic regulator in malignant cells. Silencing of miRNA expression in CLL may selectively suppress proapoptotic pathways, providing such tumors with a survival advantage. Consequently, chemotherapeutic drugs that activate miR106b could initiate a p53-independent mechanism that targets CLL cells.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
/
ARN Neoplásico
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Proteínas Nucleares
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Leucemia Linfocítica Crónica de Células B
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Regulación Leucémica de la Expresión Génica
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Apoptosis
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Proteínas Supresoras de Tumor
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MicroARNs
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Ubiquitina-Proteína Ligasas
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Proteínas de Unión al ADN
Tipo de estudio:
Prognostic_studies
Límite:
Female
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Humans
/
Male
Idioma:
En
Revista:
Blood
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos