Ectopic expression of nonliganded retinoic acid receptor β 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, Frank Rösl

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Expression of the nuclear retinoic acid receptor β2 (RARβ2) gene is often disturbed in cervical carcinoma cells. One important mechanism by which RARβ2 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 RARβ 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 RARβ 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 RARβ clones treated either with tumor necrosis factor-α or transfected with a constitutive active upstream mitogen-activated protein kinase (MEKK1Δ) 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 RARβ 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 RARβ as repressor is suggested.

Original languageEnglish (US)
Pages (from-to)45408-45416
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number44
DOIs
StatePublished - Oct 29 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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