Structure, function and modulation of retinoic acid receptor beta, a tumor suppressor.
Only one of the three-retinoic acid receptors, RARbeta, is frequently deleted or epigenetically silenced at early stages in tumor progression and there is compelling evidence that RARbeta corresponds to a tumor suppressor. Recent discoveries may help to reveal the molecular basis of the tumor suppressive action of this retinoic acid receptor subtype and provide new tools for its analysis and, possibly, therapeutic exploitation. The first concerns the recent elucidation of the crystal structure of the ligand-binding domain of the agonist-bound receptor. The second is the discovery of selective agonists, including isoform selective ligands, which are important tools to facilitate the pharmacological analysis of the tumor suppressor function of this protein in vivo. Lastly, its involvement in a retinoic acid-induced tumor-specific apoptosis program mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Herein we describe the structure, function and ligand-dependent transcription mechanism of retinoic acid receptor beta, and use rational drug design to understand the selectivity of these modulators.
Alvarez
Susana
S
Departamento de Química Orgánica, Facultad de Química, Universidade de Vigo, 36310 Vigo, Spain.
Germain
Pierre
P
Alvarez
Rosana
R
Rodríguez-Barrios
Fátima
F
Gronemeyer
Hinrich
H
de Lera
Angel R
AR
D001665:Binding Sites; D016147:Genes, Tumor Suppressor / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015533:Transcriptional Activation
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta