[Retinoids: mechanisms of action]

Area of Science:

• Molecular Biology
• Cell Biology
• Endocrinology

Background:

• Retinoids, vitamin A derivatives, are crucial regulators of cell differentiation, proliferation, and apoptosis.
• The synthesis of active metabolites, retinoic acid (RA) and 9-cis-retinoic acid, involves retinol and retinaldehyde.
• The discovery of nuclear retinoic acid receptors (NRR) in 1987 significantly advanced the understanding of retinoid action.

Purpose of the Study:

• To elucidate the structure and function of Retinoid Nuclear Receptors (RNR).
• To differentiate between Retinoic Acid Receptors (RAR) and Retinoid X Receptors (RXR) and their ligands.
• To describe the mechanism of NRR-mediated gene regulation.

Main Methods:

• Identification and characterization of nuclear retinoic acid receptors (RNR).
• Classification of RNR into RAR and RXR families, each with isotypes and isoforms.
• Analysis of NRR structural domains (A-F) and their functions in ligand binding and DNA interaction.

Main Results:

• Two families of RNR exist: RAR (ligand: RA) and RXR (ligand: 9-cis-retinoic acid).
• Synthetic retinoids like isotretinoin, acitretin, tazarotene, adapalene (RAR ligands), bexarotene (RXR ligand), and alitretinoin (panagonist) were identified.
• NRR function through dimerization (homo- or heterodimers) to bind specific DNA sequences, recruiting coactivators to activate transcription.

Conclusions:

• Retinoid action is mediated by NRR, which form dimers to regulate gene expression.
• The diverse families, isotypes, and isoforms of RNR allow for complex regulatory networks.
• Ligand binding to NRR initiates a cascade involving coactivator recruitment and transcriptional activation, with retinoids degraded by cytochrome P450 enzymes.