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Identification of the AP1-antagonism domain of retinoic acid receptors

D DiSepio1, M Sutter, A T Johnson

  • 1Department of Biology, Allergan Inc., Irvine, California 92713, USA.

Molecular Cell Biology Research Communications : MCBRC
|March 8, 1999
PubMed

Insights

Retinoids, through retinoic acid receptors (RARs), inhibit cell proliferation by antagonizing AP1. This study identifies the specific RAR regions involved in this interaction, suggesting additional cofactors beyond CBP mediate this effect.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Retinoids are crucial therapeutics for various conditions, including psoriasis, acne, and cancer.
  • Retinoic acid receptors (RARs) mediate retinoid effects, partly through antagonism of AP1-driven gene expression.
  • AP1, a transcription factor complex, drives cell growth and proliferation, and its dysregulation is implicated in diseases.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the interaction between RARs and AP1.
  • To identify the specific domains within RARs responsible for AP1 antagonism.
  • To investigate the role of cofactors, including CREB binding protein (CBP), in RAR-AP1 cross-regulation.

Main Methods:

  • Identification of RAR regions critical for AP1 antagonism.
  • Assays to assess the inhibitory effect of monomeric RAR and RAR-RXR heterodimers on AP1 reporter gene expression.
  • Analysis of the role of cofactors in mediating RAR-AP1 transrepression.

Main Results:

  • The AP1 antagonism domain of RAR comprises the core DNA binding domain and the hydrophobic zipper region.
  • Both monomeric RAR and RAR-RXR heterodimers effectively inhibit AP1-dependent gene expression.
  • Evidence suggests that cofactors beyond CBP are involved in the mutual repression between RARs and AP1.

Conclusions:

  • Specific regions of RAR are essential for antagonizing AP1 activity.
  • RARs, in both monomeric and heterodimeric forms, suppress AP1-driven gene expression.
  • The cross-regulation between RARs and AP1 involves limiting cofactors, with CBP being one but not the sole factor.

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