Regulation of nuclear receptor activity by intracellular signals and ligands

根据我们以前发现的PPARg的内源性配体，我们假设细胞外信号分子不仅通过其细胞内的代谢产物作为配体来调节PPARg的活性，而且还通过膜相关受体引起的细胞内信号来调节PPARg的活性。为了分析PPARg活性的时空调节，我们开发了一种新型的报告系统，通过该系统可以同时检测到6种独立的转录活性。我们发现，只有在SDP-1存在的情况下，磷酸化表达才能单独诱导PPARg蛋白的稳定，并阻止PPARg蛋白的核输出。我们还分析了在德国肥胖者中发现的PPARg突变对磷酸化依赖调节的影响，发现P85Q突变阻断了SDP-1的作用。因此，我们得出结论，磷酸化信号以不同于配体的机制调节PPARg的活性。

According to our previous findings of endogenous ligands for PPARg, we hypothesized that extracellular signaling molecules regulate PPARg activity through not only their intracellular metabolites acting as ligands, but also intracellular signals evoked by membrane associated receptors.To analyze the temporal and spatial regulation of PPARg activity, we developed novel reporter system, by which six independent transcriptional activities were simultaneously detected. We found that expression of phosphorylation induced stabilization of PPARg proteins by itself and blocked nuclear export of PPARg protein only in the presence of SDP-1. We also analyzed the effects of PPARg mutation identified in German obese subjects on the phoshphorylation-dependent regulation, and found that P85Q mutation blocked the effects of SDP-1. Thus, we conclude that phosphorylation signal regulates PPARg activity in the distinct mechanism from that of ligands.