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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Caspase 9 / genetics
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Caspase 9 / metabolism
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Cell Survival / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression Regulation, Leukemic*
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Gene Silencing
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HeLa Cells
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Humans
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K562 Cells
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Male
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Tumor Protein p73
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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DNA-Binding Proteins
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MIRN106 microRNA, human
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MicroRNAs
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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Repressor Proteins
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TP53 protein, human
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TP73 protein, human
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Tumor Protein p73
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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ITCH protein, human
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Ubiquitin-Protein Ligases
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CASP9 protein, human
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Caspase 9