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Molecular and Cellular Biology, May 2004, p. 4465-4475, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4465-4475.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Reduced Intranuclear Mobility of APL Fusion Proteins Accompanies Their Mislocalization and Results in Sequestration and Decreased Mobility of Retinoid X Receptor {alpha}

Shuo Dong,1,2 David L. Stenoien,3 Jihui Qiu,1 Michael A. Mancini,3 and David J. Tweardy1*

Section of Infectious Disease, Department of Medicine,1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030,3 Shanghai Institute of Hematology, Shanghai Rui-Jin Hospital, Shanghai 200025, People's Republic of China2

Received 30 October 2003/ Returned for modification 13 January 2004/ Accepted 12 February 2004

Acute promyelocytic leukemia (APL) cells contain one of five chimeric retinoic acid {alpha}-receptor (RAR{alpha}) genes (X-RAR{alpha}) created by chromosomal translocations or deletion; each generates a fusion protein thought to transcriptionally repress RAR{alpha} target genes and block myeloid differentiation by an incompletely understood mechanism. To gain spatiotemporal insight into these oncogenic processes, we employed fluorescence microscopy and fluorescence recovery after photobleaching (FRAP). Fluorescence microscopy demonstrated that the intracellular localization of each of the X-RAR{alpha} proteins was distinct from that of RAR{alpha} and established which portion(s) of each X-RAR{alpha} protein—X, RAR, or both—contributed to its altered localization. Using FRAP, we demonstrated that the intranuclear mobility of each X-RAR{alpha} was reduced compared to that of RAR{alpha}. In addition, the mobility of each X-RAR{alpha} was reduced further by ligand addition, in contrast to RAR{alpha}, which showed no change in mobility when ligand was added. Both the reduced baseline mobility of X-RAR{alpha} and the ligand-induced slowing of X-RAR{alpha} could be attributed to the protein interaction domain contained within X. RXR{alpha} aberrantly colocalized within each X-RAR{alpha}; colocalization of RXR{alpha} with promyelocytic leukemia (PML)-RAR{alpha} resulted in reduced mobility of RXR{alpha}. Thus, X-RAR{alpha} may interfere with RAR{alpha} through its aberrant nuclear dynamics, resulting in spatial and temporal sequestration of RXR{alpha} and perhaps other nuclear receptor coregulators critical for myeloid differentiation.

* Corresponding author. Mailing address: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 286, Room N1319, Houston, TX 77030. Phone: (713) 798-8918. Fax: (713) 798-8948. E-mail: dtweardy{at}bcm.tmc.edu.

Molecular and Cellular Biology, May 2004, p. 4465-4475, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4465-4475.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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