Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RARalpha.
PML-RARalpha is the causative oncogene in 5% to 10% of the cases of acute myeloid leukemia. At physiological concentrations of retinoic acid, PML-RARalpha silences RARalpha target genes, blocking differentiation of the cells. At high concentrations of ligand, it (re)activates the transcription of target genes, forcing terminal differentiation. The study of RARalpha target genes that mediate this differentiation has identified several genes that are important for proliferation and differentiation control in normal and malignant hematopoietic cells. In this paper, we show that the PML-RARalpha fusion protein not only interferes with the transcription of regular RARalpha target genes. We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein.
van Wageningen
Sake
S
Central Hematology Laboratory and Department of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Breems-de Ridder
Marleen C
MC
Nigten
Jeannet
J
Nikoloski
Gorica
G
Erpelinck-Verschueren
Claudia A J
CA
Löwenberg
Bob
B
de Witte
Theo
T
Tenen
Daniel G
DG
van der Reijden
Bert A
BA
Jansen
Joop H
JH
D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D023081:CCAAT-Binding Factor; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D016329:Sp1 Transcription Factor; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D004247:DNA