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

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

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The aberrant association of promyelocytic leukemia protein-retinoic acid receptor-α (PML-RARα) with corepressor complexes is generally thought to contribute to the ability of PML-RARα to regulate transcription. We report here that PML-RARα acquires aberrant association with coactivators. We show that endogenous PML-RARα interacts with the histone acetyltransferases CBP, p300, and SRC-1 in a hormone-independent manner, an association not seen for RARα. 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-RARα sequesters and colocalizes with coactivators. These observations correlate with the ability of PML-RARα 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-RARα 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-RARα and coactivators contributes to its ability to regulate gene expression.

Original languageEnglish (US)
Pages (from-to)18584-18596
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number25
DOIs
StatePublished - Jun 22 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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