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Cell Growth & Differentiation Vol. 13, 173-183, April 2002
© 2002 American Association for Cancer Research

The Retinoic Acid Receptor {alpha} (RAR{alpha}) Chimeric Proteins PML-, PLZF-, NPM-, and NuMA-RAR{alpha} Have Distinct Intracellular Localization Patterns1

Jeff L. Hummel, Tong Zhang, Richard A. Wells and Suzanne Kamel-Reid2

The Institute of Medical Sciences [J. L. H., R. A. W., S. K-R.] and Department of Laboratory Medicine and Pathobiology [S. K-R.], University of Toronto, Toronto, Ontario, M5S 1A8; The Ontario Cancer Institute, The Department of Pathology, The University Health Network, Toronto, Ontario, M5G 2M9 [J. L. H., T. Z., S. K-R.], Canada

Retinoic acid receptor {alpha} (RAR{alpha}) gene rearrangement by reciprocal chromosome translocation is the molecular signature of acutepromyelocytic leukemia (APL). Disruption of RAR{alpha} function appears to be the likely cause of aberrant myelopoiesis observed in APL, because PML-RAR{alpha} expression has been shown to deregulate the transcription of genes that control myelopoiesis. To target RAR{alpha} chimeric proteins, we engineered epitope-tagged versions of PML-RAR{alpha}, PLZF-RAR{alpha}, NPM-RAR{alpha}, and NuMA-RAR{alpha} (X-RAR{alpha}V5) and generated a panel of stable COS cell lines expressing X-RAR{alpha}V5. Protein fractionation and Western analysis of these COS lines reveal that X-RAR{alpha} proteins localize to both the cytoplasm and nucleus. NPM-RAR{alpha} is predominantly nuclear whereas NuMA-RAR{alpha} is predominantly cytoplasmic. Confocal immunofluorescent microscopy reveals that PML-RAR{alpha} and PLZF-RAR{alpha} share a primarily diffuse nuclear pattern that excludes the nucleolus. NPM-RAR{alpha} is also diffuse in the nucleus but, in contrast to PML-RAR{alpha} and PLZF-RAR{alpha}, is strongly associated with the nucleolus. Strikingly, NuMA-RAR{alpha} predominantly localizes throughout the cytoplasm in a microspeckled pattern. We further demonstrate that NPM and NuMA interact with NPM-RAR{alpha} and NuMA-RAR{alpha}, respectively. The distinct intracellular localization patterns and the shared ability of X-RAR{alpha} to interact with their respective RAR{alpha} partner proteins (X) further support the hypothesis that deregulation of these partners may play a role in APL pathogenesis.




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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2002 by the American Association of Cancer Research.