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Molecular and Cellular Biology, March 2002, p. 1446-1459, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1446-1459.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Chromosomal Integration of Retinoic Acid Response Elements Prevents Cooperative Transcriptional Activation by Retinoic Acid Receptor and Retinoid X Receptor

Bruno Lefebvre,^1, Céline Brand,² Philippe Lefebvre,^2* and Keiko Ozato¹

Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,¹ INSERM U459 and Ligue Nationale contre le Cancer, Faculté de Médecine Henri Warembourg, 59045 Lille Cedex, France²

Received 29 August 2001/ Returned for modification 12 October 2001/ Accepted 29 November 2001

All-trans-retinoic acid receptors (RAR) and 9-cis-retinoic acid receptors (RXR) are nuclear receptors known to cooperatively activate transcription from retinoid-regulated promoters. By comparing the transactivating properties of RAR and RXR in P19 cells using either plasmid or chromosomal reporter genes containing the mRARß2 gene promoter, we found contrasting patterns of transcriptional regulation in each setting. Cooperativity between RXR and RAR occurred at all times with transiently introduced promoters, but was restricted to a very early stage (<3 h) for chromosomal promoters. This time-dependent loss of cooperativity was specific for chromosomal templates containing two copies of a retinoid-responsive element (RARE) and was not influenced by the spacing between the two RAREs. This loss of cooperativity suggested a delayed acquisition of RAR full transcriptional competence because (i) cooperativity was maintained at RAR ligand subsaturating concentrations, (ii) overexpression of SRC-1 led to loss of cooperativity and even to strong repression of chromosomal templates activity, and (iii) loss of cooperativity was observed when additional cis-acting response elements were activated. Surprisingly, histone deacetylase inhibitors counteracted this loss of cooperativity by repressing partially RAR-mediated activation of chromosomal promoters. Loss of cooperativity was not correlated to local histone hyperacetylation or to alteration of constitutive RNA polymerase II (RNAP) loading at the promoter region. Unexpectedly, RNAP binding to transcribed regions was correlated to the RAR activation state as well as to acetylation levels of histones H3 and H4, suggesting that RAR acts at the mRARß promoter by triggering the switch from an RNA elongation-incompetent RNAP form towards an RNA elongation-competent RNAP.

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* Corresponding author. Mailing address: INSERM U459, Faculté de Médecine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France. Phone: 33.3.20626876. Fax: 33.3.20626884. E-mail: p.lefebvre{at}lille.inserm.fr.

Present address: Laboratoire de Dynamique Nucléaire et Plasticité du Génôme (UMR 218 du CNRS), Institut Curie/Section de Recherche, 75231 Paris Cedex 05, France.

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Molecular and Cellular Biology, March 2002, p. 1446-1459, Vol. 22, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.5.1446-1459.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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