Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RAR alpha
| Autor: | Sake van Wageningen, Joop H. Jansen, Gorica Nikoloski, Claudia A.J. Erpelinck-Verschueren, Marleen C. Breems-de Ridder, Bob Löwenberg, Theo de Witte, Daniel G. Tenen, Jeannet Nigten, Bert A. van der Reijden |
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| Přispěvatelé: | Hematology, Virology |
| Rok vydání: | 2008 |
| Předmět: |
Inhibitor of Differentiation Protein 1
Transcriptional Activation Oncogene Proteins Fusion Receptors Retinoic Acid Sp1 Transcription Factor Molecular Sequence Data Immunology Tretinoin Biology Retinoid X receptor Biochemistry Metabolism transport and motion [NCMLS 2] Transactivation Leukemia Promyelocytic Acute Immune Regulation [NCMLS 2] Translational research [ONCOL 3] Transcription (biology) Cell Line Tumor Iron metabolism [IGMD 7] Humans Promoter Regions Genetic Transcription factor Molecular diagnosis prognosis and monitoring [UMCN 1.2] Sp1 transcription factor Retinoic Acid Receptor alpha Immunotherapy gene therapy and transplantation [UMCN 1.4] Promoter DNA Cell Biology Hematology Molecular biology Fusion protein Up-Regulation Pathogenesis and modulation of inflammation [N4i 1] Retinoid X Receptors CCAAT-Binding Factor Retinoic acid receptor alpha embryonic structures Protein Binding |
| Zdroj: | Blood, 111(3), 1634-1643. American Society of Hematology Blood, 111, 3, pp. 1634-43 Blood, 111, 1634-43 |
| ISSN: | 0006-4971 |
| Popis: | PML-RARα is the causative oncogene in 5% to 10% of the cases of acute myeloid leukemia. At physiological concentrations of retinoic acid, PML-RARα silences RARα 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 RARα 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-RARα fusion protein not only interferes with the transcription of regular RARα target genes. We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wild-type RARα/RXR. Our data support a model in which the PML-RARα 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. |
| Databáze: | OpenAIRE |
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