Aberrant Association of Promyelocytic Leukemia Protein-Retinoic Acid Receptor-α with Coactivators Contributes to Its Ability to Regulate Gene Expression

Yu Liu,Heng Liu,Minh Lam,Hung-Ying Kao,Erin L Reineke

doi:10.1074/jbc.m700330200

Yu Liu, Heng Liu + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m700330200

Copy DOI

Abstract

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.

Highlights

Acute promyelocytic leukemia (APL)3 is a disease in which a terminal differentiation block of myeloid precursors occurs at
We found that overexpression of promyelocytic leukemia (PML)-RAR␣ decreases transcription activation by the glucocorticoid receptor (GR) and CBF1
The observations that PML-RAR␣ requires higher concentrations of hormone to dissociate from corepressors and that both corepressor- and coactivator-binding domains overlap in the modeled nuclear receptor ligand-binding domain (LBD) suggested that PML-RAR␣ may interact with both sets of coregulators differently from wild-type RAR␣ [23]

Summary

Introduction

Acute promyelocytic leukemia (APL) is a disease in which a terminal differentiation block of myeloid precursors occurs at. In contrast to the action of histone deacetylases, histone acetyltransferases acetylate histone tails, resulting in weaker associations of histones with chromatin and creating a local environment conducive for binding of the general transcription machinery to the target promoter. These notions are ing protein; LBD, ligand-binding domain; GR, glucocorticoid receptor; ATRA, all-trans-retinoic acid; HA, hemagglutinin; PBS, phosphate-buffered saline; GST, glutathione S-transferase; RID, receptor interaction domain; RT, reverse transcription; GILZ, glucocorticoid-induced leucine zipper. It has been proposed that these consensus motifs signify a common mechanism of transcription regulation throughout the nuclear receptor family members

Methods

Results

Conclusion