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Molecular and Cellular Biology, July 2002, p. 4522-4534, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4522-4534.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Retinoic Acid Receptors Inhibit AP1 Activation by Regulating Extracellular Signal-Regulated Kinase and CBP Recruitment to an AP1-Responsive Promoter

Madjid Benkoussa, Céline Brand, Marie-Hélène Delmotte,,{dagger} Pierre Formstecher, and Philippe Lefebvre*

INSERM U 459 and Ligue Nationale Contre le Cancer, Faculté de Médecine Henri Warembourg, 59045 Lille Cedex, France

Received 16 October 2001/ Returned for modification 13 December 2001/ Accepted 27 March 2002

Retinoids exhibit antineoplastic activities that may be linked to retinoid receptor-mediated transrepression of activating protein 1 (AP1), a heterodimeric transcription factor composed of fos- and jun-related proteins. Here we show that transcriptional activation of an AP1-regulated gene through the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway (MAPKERK) is characterized, in intact cells, by a switch from a fra2-junD dimer to a junD-fosB dimer loading on its promoter and by simultaneous recruitment of ERKs, CREB-binding protein (CBP), and RNA polymerase II. All-trans-retinoic acid (atRA) receptor (RAR) was tethered constitutively to the AP1 promoter. AP1 transrepression by retinoic acid was concomitant to glycogen synthase kinase 3 activation, negative regulation of junD hyperphosphorylation, and to decreased RNA polymerase II recruitment. Under these conditions, fra1 loading to the AP1 response element was strongly increased. Importantly, CBP and ERKs were excluded from the promoter in the presence of atRA. AP1 transrepression by retinoids was RAR and ligand dependent, but none of the functions required for RAR-mediated transactivation was necessary for AP1 transrepression. These results indicate that transrepressive effects of retinoids are mediated through a mechanism unrelated to transcriptional activation, involving the RAR-dependent control of transcription factors and cofactor assembly on AP1-regulated promoters.

* Corresponding author. Mailing address: INSERM U 459, Faculté de Médecine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France. Phone: 33-3-20-62-68-87. Fax: 33-3-20-62-68-84. E-mail: p.lefebvre{at}lille.inserm.fr.

{dagger} Present address: Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605.

Molecular and Cellular Biology, July 2002, p. 4522-4534, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4522-4534.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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