Alvarez Susana, Germain Pierre, Alvarez Rosana, Rodríguez-Barrios Fátima, Gronemeyer Hinrich, de Lera Angel R
Departamento de Química Orgánica, Facultad de Química, Universidade de Vigo, 36310 Vigo, Spain.
Int J Biochem Cell Biol. 2007;39(7-8):1406-15. doi: 10.1016/j.biocel.2007.02.010. Epub 2007 Feb 22.
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.
在三种维甲酸受体中，只有维甲酸受体β（RARβ）在肿瘤进展的早期阶段经常被缺失或发生表观遗传沉默，并且有确凿的证据表明RARβ相当于一种肿瘤抑制因子。最近的发现可能有助于揭示这种维甲酸受体亚型的肿瘤抑制作用的分子基础，并为其分析以及可能的治疗应用提供新工具。第一个方面涉及最近对激动剂结合型受体的配体结合结构域晶体结构的阐明。第二个方面是发现了选择性激动剂，包括亚型选择性配体，这些是促进体内对该蛋白的肿瘤抑制功能进行药理学分析的重要工具。最后一个方面是它参与由肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的维甲酸诱导的肿瘤特异性凋亡程序。在此，我们描述维甲酸受体β的结构、功能和配体依赖性转录机制，并利用合理药物设计来了解这些调节剂的选择性。
