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J. Biol. Chem., Vol. 282, Issue 46, 33421-33434, November 16, 2007

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Retinoic Acid Receptor Isotype Specificity in F9 Teratocarcinoma Stem Cells Results from the Differential Recruitment of Coregulators to Retinoic Acid Response Elements^*

Robert F. Gillespie and Lorraine J. Gudas¹

From the Molecular Biology Program, Weill Graduate School of Medical Sciences, Cornell University and Pharmacology Department, Weill Medical College of Cornell University, New York, New York 10021

The retinoic acid receptor (RAR) , ₂, and isotypes each regulate specific subsets of target genes in F9 teratocarcinoma stem cells. We used chromatin immunoprecipitation assays to monitor the association of RAR, retinoic X receptor (RXR) , and coregulators with the RAR₂, Hoxa1, and Cyp26A1 retinoic acid response elements (RAREs) in F9 wild type and RAR, -₂, and - null cells. Additionally we quantitatively monitored expression of the corresponding mRNAs. We demonstrated that the association of RAR and/or RXR with a RARE was not sufficient for retinoic acid (RA)-mediated transcription of the corresponding target gene. However, the ability of RAR and/or RXR to recruit pCIP (AIB1/ACTR/RAC-3/TRAM-1/SRC-3) and p300 to a RARE did correlate with RA-associated transcription of target mRNAs. Therefore, the specific functions of the RAR isotypes do not manifest at the level of their DNA binding but rather from a differential ability to recruit specific components of the transcriptional machinery. We also demonstrated that RA-mediated displacement of the polycomb group protein SUZ12 from a RARE was inhibited in the absence of RAR. Thus, transcriptional components of the RAR signaling pathway are specifically required for displacement of SUZ12 from RAREs during RA-mediated differentiation of F9 cells.

Received for publication, June 12, 2007 , and in revised form, September 12, 2007.

^* This work was supported by National Institutes of Health Grants RO1CA043796 (to L. J. G.) and RO1DK454560 (partial support to R. G.; principal investigator, L. Freedman). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Weill Medical College of Cornell University, 1300 York Ave., Rm. E-409, New York, NY, 10021. Tel.: 212-746-6250; Fax: 212-746-8858; E-mail: ljgudas{at}med.cornell.edu.

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