Aberrant association of promyelocytic leukemia protein-retinoic acid receptor-alpha with coactivators contributes to its ability to regulate gene expression.

The aberrant association of promyelocytic leukemia protein-retinoic acid receptor-alpha (PML-RARalpha) with corepressor complexes is generally thought to contribute to the ability of PML-RARalpha to regulate transcription. We report here that PML-RARalpha acquires aberrant association with coactivators. We show that endogenous PML-RARalpha interacts with the histone acetyltransferases CBP, p300, and SRC-1 ...
in a hormoneindependent manner, an association not seen for RARalpha. This hormone-independent coactivator binding activity requires an intact ligand-binding domain and the NR box of the coactivators. Confocal microscopy studies demonstrate that exogenous PML-RARalpha sequesters and colocalizes with coactivators. These observations correlate with the ability of PML-RARalpha to attenuate the transcription activation of the Notch signaling downstream effector, CBF1, and of the glucocorticoid receptor. This includes attenuation of the glucocorticoid-induced leucine zipper (GILZ) and FLJ25390 target genes of the endogenous glucocorticoid receptor. Furthermore, treatment of NB4 cells with all-trans-retinoic acid, which promotes PML-RARalpha degradation, resulted in increased activation of GILZ. On the basis of these findings, we propose a model in which the hormone-independent association between PML-RARalpha and coactivators contributes to its ability to regulate gene expression.
Mesh Terms:
Animals, Cell Line, Gene Expression Regulation, Neoplastic, Glutathione Transferase, HL-60 Cells, Humans, Microscopy, Fluorescence, Models, Biological, Neoplasm Proteins, Nuclear Proteins, Plasmids, Protein Binding, Protein Structure, Tertiary, Receptors, Notch, Receptors, Retinoic Acid, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins
J. Biol. Chem.
Date: Jun. 22, 2007
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