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Blood, 15 July 2007, Vol. 110, No. 2, pp. 640-650. Prepublished online as a Blood First Edition Paper on April 9, 2007; DOI 10.1182/blood-2006-11-059048. This Article Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2006-11-059048v1 110/2/640    most recent Alert me when this article is cited Alert me if a correction is posted 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 Hattori, H. Articles by Luo, H. R Search for Related Content PubMed PubMed Citation Articles by Hattori, H. Articles by Luo, H. R Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 21, 2006 Accepted April 5, 2007 RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells Hidenori Hattori, Xueqing Zhang, Yonghui Jia, Kulandayan K Subramanian, Hakryul Jo, Fabien Loison, Peter E Newburger, and Hongbo R Luo* Dept of Pathology, Joint Program in Transfusion Medicine, Harvard Medical School Department of Family Lab Medicine & Children's Hospital Boston, Boston, MA, United States Dept of Pediatrics, University of Massachusetts Medical School, Worcester, MA, United States * Corresponding author; email: hongbo.luo{at}childrens.harvard.edu. All-trans-retinoic acid (ATRA) has been widely used in differentiation therapy for acute promyelocytic leukemia (APL). ATRA binds to retinoic acid receptor (RAR) and triggers the formation of the transcription coactivator complex, which leads to changes in gene expression, APL cell cycle arrest and differentiation, and clinical remission. The mechanisms responsible for ATRA's beneficial effects are still ill-defined. Here, we conducted a large scale unbiased shRNA screen aiming to identify mediators of ATRA-induced differentiation and growth arrest of APL cells. Twenty-six proteins were identified. They cover a wide range of cellular functions, including gene expression, intracellular signaling, cell death control, stress responses, and metabolic regulation, indicating the complexity of ATRA-induced cell growth control and differentiation in APL. One of these proteins, the ubiquitin-conjugating enzyme UBE2D3 is up-regulated in ATRA-treated acute promyelocytic NB4 cells. UBE2D3 is physically associated with cyclin D1 and mediates ATRA-induced cyclin D1 degradation. Knocking down UBE2D3 by RNAi leads to blockage of ATRA-induced cyclin D1 degradation and cell cycle arrest. Thus, our results highlight the involvement of ubiquitin-mediated proteolysis pathway in ATRA-induced cell cycle arrest, and provide a novel strategy for modulating ATRA-elicited cellular effects. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ATRA: Finding targeted APL therapy targets Arati Khanna-Gupta and Nancy Berliner Blood 2007 110: 476-477. [Full Text] [PDF] This article has been cited by other articles: D. Nowak, D. Stewart, and H. P. Koeffler Differentiation therapy of leukemia: 3 decades of development Blood, April 16, 2009; 113(16): 3655 - 3665. [Abstract] [Full Text] [PDF] X. Zhang, Z. Lian, C. Padden, M. B. Gerstein, J. Rozowsky, M. Snyder, T. R. Gingeras, P. Kapranov, S. M. Weissman, and P. E. Newburger A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster Blood, March 12, 2009; 113(11): 2526 - 2534. [Abstract] [Full Text] [PDF]

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