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J. Biol. Chem., Vol. 279, Issue 44, 45408-45416, October 29, 2004

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Ectopic Expression of Nonliganded Retinoic Acid Receptor Abrogates AP-1 Activity by Selective Degradation of c-Jun in Cervical Carcinoma Cells^*

Johanna De-Castro Arce, Ubaldo Soto, Jan van Riggelen, Elisabeth Schwarz, Harald zur Hausen, and Frank Rösl

From the Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany

Expression of the nuclear retinoic acid receptor 2 (RAR2) gene is often disturbed in cervical carcinoma cells. One important mechanism by which RAR2 can exert growth inhibitory function is based on its ability to repress the AP-1 transcription factor in a ligand-dependent manner. Because less is known about the biological effects of RAR in the absence of ligand, the corresponding cDNA was stably introduced into HPV18-positive HeLa cervical carcinoma cells. In the present study we describe a novel mechanism by which AP-1 becomes inactivated. Constitutive expression of nonliganded RAR abrogated both AP-1 binding affinity and activity by a selective degradation of the c-Jun protein as major dimerization partner, without substitution by other members of the Jun family. Blockage of the proteasomal pathway completely rescued c-Jun and reconstituted the AP-1 function. Moreover, HeLa RAR2 clones treated either with tumor necrosis factor- or transfected with a constitutive active upstream mitogen-activated protein kinase (MEKK1) also resulted in c-Jun phosphorylation and restoration of AP-1 affinity and functionality similar to that found in nontransfected parental HeLa cells. These data revealed an important cross-talk between trans-repression of AP-1 and nonliganded RAR in human papillomavirus-positive cells. Because AP-1 activity was not irreversibly disturbed, but could be switched on through activation of the Jun N-terminal kinase pathway, a model for the transient activation of AP-1 even in the presence of RAR as repressor is suggested.

Received for publication, February 19, 2004 , and in revised form, June 28, 2004.

^* 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 a figure.

Present address: Dept. of Biochemistry, Loma Linda University, Loma Linda, CA 92350.

To whom correspondence should be addressed: Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Tel.: 49-6221-42-4900; Fax: 49-6221-42-4902; E-mail: F.Roesl{at}dkfz.de.

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