Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers.
The t(15;17) chromosomal translocation in acute promyelocytic leukemia (APL) generates the PML-RARalpha fusion protein. The recruitment of nuclear receptor corepressor SMRT/N-CoR and subsequent repression of retinoid target genes is critical for the oncogenic function of PML-RARalpha. Here we show that the ability of PML-RARalpha to form homodimers is both necessary and sufficient for its increased binding efficiency to corepressor and inhibitory effects on hormonal responses in myeloid differentiation. We further provide evidence that altered stoichiometric interaction of SMRT with PML-RARalpha homodimers may underlie these processes. Finally, we demonstrate that a RXR AF2 mutant recapitulates many biochemical and functional properties of PML-RARalpha. Taken together, our results provide an example that altered dimerization of a transcription factor can be directly linked to cellular transformation and implicate dimerization interfaces of oncogenes as potential drug targets.
Lin
R J
RJ
Graduate Program in Molecular Pathology, University of California San Diego School of Medicine, La Jolla 92093, USA.
Evans
R M
RM
D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D002762:Cholecalciferol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D015973:Gene Expression Regulation, Leukemic; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000235:genetics; D008957:Models, Genetic; D009000:Monocytes / Q000166:cytology; D009363:Neoplasm Proteins / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D002762:Cholecalciferol; D014212:Tretinoin