+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: not found

      Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation.


      Apoptosis, Apoptosis Regulatory Proteins, genetics, metabolism, Caspase 9, Cell Survival, DNA-Binding Proteins, Female, Gene Expression Regulation, Leukemic, Gene Silencing, HeLa Cells, Humans, K562 Cells, Leukemia, Lymphocytic, Chronic, B-Cell, Male, MicroRNAs, Nuclear Proteins, Proto-Oncogene Proteins, RNA, Messenger, RNA, Neoplasm, Repressor Proteins, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          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.

          Related collections

          Author and article information



          Comment on this article