Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization.
The pathogenesis of acute promyelocytic leukemia involves the transcriptional repression of master genes of myeloid differentiation by the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARA) oncogene. PML-enforced RARA homodimerization allows the tighter binding of corepressors, silencing RARA target genes. In addition, homodimerization dramatically extends the spectrum of DNA-binding sites of the fusion protein compared with those of normal RARA. Yet, any contribution of these two properties of PML/RARA to differentiation arrest and immortalization of primary mouse hematopoietic progenitors was unknown. We demonstrate that dimerization-induced silencing mediator of retinoid and thyroid receptors (SMRT)-enhanced binding and relaxed DNA-binding site specificity are both required for efficient immortalization. Thus, enforced RARA dimerization is critical not only for triggering transcriptional repression but also for extending the repertoire of target genes. Our studies exemplify how dimerization-induced gain of functions converts an unessential transcription factor into a dominant oncogenic protein.
Zhou
Jun
J
Centre National de la Recherche Scientifique Unité Mixte de Recherche 7151, Université de Paris 7, Equipe labellisée par la Ligue Nationale contre le Cancer, Hôpital St. Louis, 1 Avenue C. Vellefaux, 75475 Paris Cedex 10, France.
Pérès
Laurent
L
Honoré
Nicole
N
Nasr
Rihab
R
Zhu
Jun
J
de Thé
Hugues
H
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D052138:Genes, Neoplasm; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D047488:Retinoid X Receptors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D004247:DNA