Ligand-Independent Phosphorylation of the Glucocorticoid Receptor Integrates Cellular Stress Pathways with Nuclear Receptor Signaling
Ligand-Independent Phosphorylation of the Glucocorticoid Receptor Integrates Cellular Stress Pathways with Nuclear Receptor Signaling
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DOI：
10.1128/mcb.05866-11
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发表时间：
2011-12-01
影响因子：
5.3
通讯作者：
Cidlowski, John Anthony
中科院分区：
文献类型：
--
作者：
Galliher-Beckley, Amy Jo;Williams, Jason Grant;Cidlowski, John Anthony
糖皮质激素是通过核受体介导的基因调节来维持体内平衡的应激激素。我们已经发现，其他细胞应激因子通过人糖皮质激素受体（GR）上的一个新的非依赖于糖皮质激素的磷酸化位点Ser 134与糖皮质激素信号传导整合。Ser 134磷酸化是由多种应激激活刺激以p38丝裂原活化蛋白激酶（MAPK）依赖的方式诱导的。表达不能在Ser 134磷酸化的突变型糖皮质激素受体（S134 A-GR）的细胞显著改变了依赖于腺苷酸的全基因组转录反应和相关腺苷酸介导的细胞功能。Ser 134的磷酸化显著增加了GR与染色质启动子区域上的14-3-3类信号蛋白（14-3- 3 zeta）的zeta同种型的关联，导致选择基因的钝化的依赖于转录的应答。这些数据表明，Ser 134的磷酸化作为GR上的分子传感器，通过改变14-3- 3 zeta辅因子结合和启动子募集来监测细胞应激水平以重定向糖皮质激素调节的信号传导。这种翻译后修饰允许先前的细胞应激信号指示对糖皮质激素的转录应答。
Glucocorticoids are stress hormones that maintain homeostasis through gene regulation mediated by nuclear receptors. We have discovered that other cellular stressors are integrated with glucocorticoid signaling through a new hormone-independent phosphorylation site, Ser134, on the human glucocorticoid receptor (GR). Ser134 phosphorylation is induced by a variety of stress-activating stimuli in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Cells expressing a mutant glucocorticoid receptor incapable of phosphorylation at Ser134 (S134A-GR) had significantly altered hormone-dependent genome-wide transcriptional responses and associated hormone-mediated cellular functions. The phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform of the 14-3-3 class of signaling proteins (14-3-3zeta) on chromatin promoter regions, resulting in a blunted hormone-dependent transcriptional response of select genes. These data argue that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to redirect glucocorticoid-regulated signaling through altered 14-3-3zeta cofactor binding and promoter recruitment. This posttranslational modification allows prior cellular stress signals to dictate the transcriptional response to glucocorticoids.