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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3744-3753. Prepublished online as a Blood First Edition Paper on December 18, 2008; DOI 10.1182/blood-2008-09-178707. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2008-09-178707v1 113/16/3744    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sampath, D. Articles by Plunkett, W. Search for Related Content PubMed PubMed Citation Articles by Sampath, D. Articles by Plunkett, W. Related Collections Lymphoid Neoplasia Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation Deepa Sampath1, George A. Calin1, Vinay K. Puduvalli2, Gopal Gopisetty2, Cristian Taccioli3, Chang-Gong Liu1, Brett Ewald1, Chaomei Liu1, Michael J. Keating4, and William Plunkett1 Departments of 1 Experimental Therapeutics and 2 Neuro-oncology, University of Texas M. D. Anderson Cancer Center, Houston; 3 Comprehensive Cancer Center, Ohio State University, Columbus; and 4 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: p73, miR106b, miR34a, and Itch in chronic lymphocytic leukemia Pia Rivetti di Val Cervo, Paola Tucci, Aneela Majid, Maria Anna Lena, Massimiliano Agostini, Sergio Bernardini, Eleonora Candi, Gerry Cohen, Pierluigi Nicotera, Martin J. S. Dyer, and Gerry Melino Blood 2009 113: 6498-6499. [Full Text] [PDF] Response: Context-dependent actions of miR-106b in CLL Deepa Sampath and William Plunkett Blood 2009 113: 6499-6500. [Full Text] [PDF] This article has been cited by other articles: P. Lunghi, A. Costanzo, L. Mazzera, V. Rizzoli, M. Levrero, and A. Bonati The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting Clin. Cancer Res., November 1, 2009; 15(21): 6495 - 6502. [Abstract] [Full Text] [PDF] P. R. di Val Cervo, P. Tucci, A. Majid, M. A. Lena, M. Agostini, S. Bernardini, E. Candi, G. Cohen, P. Nicotera, M. J. S. Dyer, et al. p73, miR106b, miR34a, and Itch in chronic lymphocytic leukemia Blood, June 18, 2009; 113(25): 6498 - 6499. [Full Text] [PDF] D. Sampath and W. Plunkett Response: Context-dependent actions of miR-106b in CLL Blood, June 18, 2009; 113(25): 6499 - 6500. [Full Text] [PDF]

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