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Reduced intranuclear mobility of APL fusion proteins accompanies their mislocalization and results in sequestration and decreased mobility of retinoid X receptor

By Shuo Dong, David L. Stenoien, Jihui Qiu, Michael A. Mancini and David J. Tweardy


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

Year: 2004
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