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

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.

• Authors: 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
• Journal: Blood (Blood) Vol. 111 Issue 3 Pg. 1634-43 (Feb 01 2008) ISSN: 0006-4971 [Print] United States
• PMID: 18025157 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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