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J. Biol. Chem., Vol. 282, Issue 25, 18584-18596, June 22, 2007

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

Erin L. Reineke¹, Heng Liu, Minh Lam, Yu Liu, and Hung-Ying Kao²

From the Department of Biochemistry, School of Medicine, Case Western Reserve University, and the Research Institute of University Hospitals of Cleveland and the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106

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

Received for publication, January 12, 2007 , and in revised form, May 1, 2007.

^* This work was supported in part by National Institutes of Health Grant P30 CA43703-12 from the Confocal Microscopy Core Facility of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by Case Comprehensive Cancer Center Research Oncology Training Grant T32 CA059366-11 from NCI, National Institutes of Health.

² Recipient of American Cancer Society Grant RSG-04-052-01-GMC. To whom correspondence should be addressed: Dept. of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-1150; Fax: 216-368-3419; E-mail: hxk43{at}cwru.edu.

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