Title
RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells
UMMS Affiliation
Department of Pediatrics
Publication Date
2007-07-15
Document Type
Article
Subjects
Cell Cycle; Cell Division; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Oligonucleotide Array Sequence Analysis; *RNA Interference; RNA, Small Interfering; Signal Transduction; Tretinoin; Ubiquitin-Conjugating Enzymes
Disciplines
Hematology | Oncology | Pediatrics
Abstract
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.
DOI of Published Version
10.1182/blood-2006-11-059048
Source
Blood. 2007 Jul 15;110(2):640-50. Epub 2007 Apr 9. doi: 10.1182/blood-2006-11-059048
Journal/Book/Conference Title
Blood
Related Resources
PubMed ID
17420285
Repository Citation
Hattori, Hidenori; Zhang, Xueqing; Jia, Yonghui; Subramanian, Kulandayan K.; Jo, Hakryul; Loison, Fabien; Newburger, Peter E.; and Luo, Hongbo R., "RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells" (2007). Hematology/Oncology. 98.
https://escholarship.umassmed.edu/peds_hematology/98