Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RARalpha

Sake van Wageningen; Marleen C Breems-de Ridder; Jeannet Nigten; Gorica Nikoloski; Claudia A J Erpelinck-Verschueren; Bob Löwenberg; Theo de Witte; Daniel G Tenen; Bert A van der Reijden; Joop H Jansen

doi:10.1182/blood-2007-04-081125

Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RARalpha

Blood. 2008 Feb 1;111(3):1634-43. doi: 10.1182/blood-2007-04-081125. Epub 2007 Nov 19.

Authors

Sake van Wageningen¹, Marleen C Breems-de Ridder, Jeannet Nigten, Gorica Nikoloski, Claudia A J Erpelinck-Verschueren, Bob Löwenberg, Theo de Witte, Daniel G Tenen, Bert A van der Reijden, Joop H Jansen

Affiliation

¹ Central Hematology Laboratory and Department of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

PMID: 18025157
DOI: 10.1182/blood-2007-04-081125

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CCAAT-Binding Factor / genetics
CCAAT-Binding Factor / metabolism
Cell Line, Tumor
DNA / genetics*
DNA / metabolism
Humans
Inhibitor of Differentiation Protein 1 / genetics
Inhibitor of Differentiation Protein 1 / metabolism
Leukemia, Promyelocytic, Acute / genetics
Leukemia, Promyelocytic, Acute / pathology
Molecular Sequence Data
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism*
Promoter Regions, Genetic / genetics
Protein Binding
Receptors, Retinoic Acid / genetics
Receptors, Retinoic Acid / metabolism
Retinoic Acid Receptor alpha
Retinoid X Receptors / genetics
Retinoid X Receptors / metabolism
Sp1 Transcription Factor / genetics
Sp1 Transcription Factor / metabolism
Transcriptional Activation / drug effects
Transcriptional Activation / genetics*
Tretinoin / pharmacology
Up-Regulation

Substances

CCAAT-Binding Factor
ID1 protein, human
Inhibitor of Differentiation Protein 1
Oncogene Proteins, Fusion
RARA protein, human
Receptors, Retinoic Acid
Retinoic Acid Receptor alpha
Retinoid X Receptors
Sp1 Transcription Factor
promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
Tretinoin
DNA