Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation
Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation
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DOI：
10.1182/blood-2008-09-178707
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发表时间：
2009-04-16
期刊：
影响因子：
20.3
通讯作者：
Plunkett, William
中科院分区：
文献类型：
--
作者：
Sampath, Deepa;Calin, George A.;Plunkett, William
慢性淋巴细胞白血病（CLL）的特征在于表现出功能失调性凋亡的细胞。在这里，我们表明，去乙酰化酶抑制导致E2 F1和myc介导的转录激活的microRNA miR 106 b在原代CLL细胞。miR 106 b的诱导与E3-泛素连接酶Itch水平的下调相关。Itch蛋白水平的降低与其促凋亡底物TAp 73（p73）的相互积累以及诱导p53上调的凋亡调节因子（p53）mRNA和蛋白相关。这一事件伴随着线粒体功能障碍、半胱天冬酶-9的加工和CLL细胞的凋亡。miR 106 b在CLL细胞中的异位表达表明，瘙痒是miR 106 b的直接靶标，使得miR 106 b诱导的瘙痒减少导致p73的积累。因此，我们的研究结果确定了一种新的调节机制，其中microRNA通过介导泛素连接酶的转录后下调来调节细胞存活，从而诱导恶性细胞中的促凋亡调节因子。在CLL中沉默miRNA表达可以选择性地抑制促凋亡途径，为这种肿瘤提供生存优势。因此，激活miR 106 b的化疗药物可以启动靶向CLL细胞的p53非依赖性机制。（血。2009; 113：3744-3753）
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. (Blood. 2009; 113: 3744-3753)