Retinoic acid receptor alpha fusion to PML affects its transcriptional and chromatin-remodeling properties.
PML-RAR is an oncogenic transcription factor forming in acute promyelocytic leukemias (APL) because of a chromosomal translocation. Without its ligand, retinoic acid (RA), PML-RAR functions as a constitutive transcriptional repressor, abnormally associating with the corepressor-histone deacetylase complex and blocking hematopoietic differentiation. In the presence of pharmacological concentrations of RA, PML-RAR activates transcription and stimulates differentiation. Even though it has been suggested that chromatin alteration is important for APL onset, the PML-RAR effect on chromatin of target promoters has not been investigated. Taking advantage of the Xenopus oocyte system, we compared the wild-type transcription factor RARalpha with PML-RAR as both transcriptional regulators and chromatin structure modifiers. Without RA, we found that PML-RAR is a more potent transcriptional repressor that does not require the cofactor RXR and produces a closed chromatin configuration. Surprisingly, repression by PML-RAR occurs through a further pathway that is independent of nucleosome deposition and histone deacetylation. In the presence of RA, PML-RAR is a less efficient transcriptional activator that is unable to modify the DNA nucleoprotein structure. We propose that PML-RAR, aside from its ability to recruit aberrant quantities of histone deacetylase complexes, has acquired additional repressive mechanisms and lost important activating functions; the comprehension of these mechanisms might reveal novel targets for antileukemic intervention.
Segalla
Simona
S
Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, 21052 Busto Arsizio (VA), Italy.
Rinaldi
Laura
L
Kilstrup-Nielsen
Charlotte
C
Badaracco
Gianfranco
G
Minucci
Saverio
S
Pelicci
Pier Giuseppe
PG
Landsberger
Nicoletta
N
D000818:Animals; D019677:Artificial Gene Fusion; D001483:Base Sequence; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D014981:Xenopus
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011994:Recombinant Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin