RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit

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J Y Chen1, S Penco, J Ostrowski

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.

The EMBO Journal
|March 15, 1995
PubMed

Insights

Synthetic retinoids selectively activate retinoic acid receptor (RAR) beta while blocking RAR alpha and gamma. These compounds, like retinoic acid (RA), repress AP1 activity, dissociating transactivation from transrepression functions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • Retinoic acid receptors (RARs) are crucial nuclear receptors involved in gene regulation.
  • Understanding the distinct functions of RAR subtypes (alpha, beta, gamma) is key to developing targeted therapies.
  • AP1 (activator protein 1) is a transcription factor implicated in cell proliferation and differentiation.

Purpose of the Study:

  • To identify synthetic retinoids with specific activity profiles for RAR subtypes.
  • To investigate the dissociation of transactivation and transrepression functions of RARs.
  • To explore the role of RARs and synthetic retinoids in AP1 activity and cell proliferation.

Main Methods:

  • Utilized RAR reporter cells specific for RAR alpha, beta, or gamma.
  • Employed AP1 reporter cells to assess AP1 activity.
  • Transfected HeLa cells with reporter genes and RARs.
  • Used Ki-ras-transformed 3T3 cells as a model for cell proliferation studies.

Main Results:

  • Identified synthetic retinoids that specifically induce transactivation by RAR beta and antagonize RAR alpha and gamma.
  • Demonstrated that these synthetic retinoids, like retinoic acid (RA), repress AP1 activity, dissociating transactivation from transrepression.
  • Showed synergistic repression of AP1 activity by glucocorticoids or vitamin D3 with RA or synthetic retinoids.
  • Observed that RA, but not the dissociating retinoids, induced interleukin-6 promoter activity.
  • Found that both RA and dissociating retinoids inhibit anchorage-independent cell proliferation in Ki-ras-transformed 3T3 cells.

Conclusions:

  • Designed synthetic retinoids can selectively modulate RAR subtype activity.
  • The transactivation and transrepression functions of RARs can be functionally dissociated by specific ligands.
  • Retinoid-induced growth inhibition may be linked to AP1 transrepression, offering potential therapeutic strategies.

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