Shao D, Rangwala S M, Bailey S T, Krakow S L, Reginato M J, Lazar M A
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Nature. 1998 Nov 26;396(6709):377-80. doi: 10.1038/24634.
Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-gamma (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation and modulates insulin sensitivity, cell proliferation and inflammatory processes. PPAR-gamma ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-gamma is induced by binding diverse ligands, including natural fatty acid derivatives, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. Ligand binding by PPAR-gamma, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor. Here we show that ligand binding by PPAR-gamma is regulated by intramolecular communication between its amino-terminal A/B domain and its carboxy-terminal LBD. Modification of the A/B domain, for example by physiological phosphorylation by MAP kinase, reduces ligand-binding affinity, thus negatively regulating the transcriptional and biological functions of PPAR-gamma. The ability of the A/B domain to regulate ligand binding has important implications for the evaluation and mechanism of action of potentially therapeutic ligands that bind PPAR-gamma and that are likely to extend to other members of the nuclear-receptor superfamily.
与细胞核中的受体结合对于亲脂性激素和配体的作用至关重要。PPAR-γ（过氧化物酶体增殖物激活受体）是一种核激素受体，介导脂肪细胞分化并调节胰岛素敏感性、细胞增殖和炎症过程。PPAR-γ配体与致动脉粥样硬化泡沫细胞的形成有关，并被视为潜在的癌症治疗药物。PPAR-γ的转录活性可通过结合多种配体来诱导，这些配体包括天然脂肪酸衍生物、抗糖尿病噻唑烷二酮类药物以及非甾体抗炎药。PPAR-γ以及整个核受体超家族与配体的结合，是受体羧基末端配体结合域（LBD）的一种独立特性。在此我们表明，PPAR-γ与配体的结合受其氨基末端A/B结构域与其羧基末端LBD之间的分子内通讯调控。例如，通过丝裂原活化蛋白激酶进行的生理性磷酸化对A/B结构域进行修饰，会降低配体结合亲和力，从而对PPAR-γ的转录和生物学功能产生负调控作用。A/B结构域调节配体结合的能力对于评估与PPAR-γ结合的潜在治疗性配体的作用机制具有重要意义，并且可能延伸至核受体超家族的其他成员。
