Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.
Details
Serval ID
serval:BIB_06DDCEAF003C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424[print], 0027-8424[linking]
Publication state
Published
Issued date
08/1995
Volume
92
Number
16
Pages
7401-7405
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.
Keywords
Animals, Binding Sites, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, DNA/metabolism, Drosophila, Hela Cells, Humans, Leukemia, Promyelocytic, Acute/genetics, Leukemia, Promyelocytic, Acute/metabolism, Mice, Neoplasm Proteins/chemistry, Neoplasm Proteins/genetics, Oncogene Proteins, Fusion/chemistry, Oncogene Proteins, Fusion/genetics, Protein Conformation, Receptors, Cytoplasmic and Nuclear/metabolism, Receptors, Retinoic Acid/metabolism, Retinoid X Receptors, Signal Transduction, Transcription Factors/metabolism, Transcriptional Activation, Translocation, Genetic
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 17:04
Last modification date
20/08/2019 13:29