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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.

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NEOPLASIA

RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells

Hidenori Hattori1, Xueqing Zhang2, Yonghui Jia1, Kulandayan K. Subramanian1, Hakryul Jo1, Fabien Loison, Peter E. Newburger2, and Hongbo R. Luo1

1 Department of Pathology, Joint Program in Transfusion Medicine, Harvard Medical School, Department of Lab Medicine, Children's Hospital Boston; 2 Department of Pediatrics, University of Massachusetts Medical School, Worcester

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 short hairpin RNA (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 RNA interference (RNAi) leads to blockage of ATRA-induced cyclin D1 degradation and cell-cycle arrest. Thus, our results highlight the involvement of the ubiquitin-mediated proteolysis pathway in ATRA-induced cell-cycle arrest and provide a novel strategy for modulating ATRA-elicited cellular effects.


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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]





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