Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase

The mitogen-activated protein kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 phosphorylate and activate transcription factors that promote proliferative and inflammatory responses, whereas glucocorticoid receptor (GR) activation inhibits cell growth and inflammation. We demonstrate that JNK and ERK but not p38 phosphorylate GR in vitro primarily at Ser-246. Selective activation of either ERK or JNK in vivo inhibits GR-mediated transcriptional activation, which depends on receptor phosphorylation at Ser-246 by JNK but not ERK. Thus, JNK inhibits GR transcriptional activation by direct receptor phosphorylation, whereas ERK does so indirectly. We propose that phosphorylation of GR by JNK or of a GR cofactor by ERK provides mechanisms to ensure the rapid inhibition of GR-dependent gene expression when it conflicts with mitogenic or proinflammatory signals.

丝裂原活化蛋白激酶（mitogen-activated protein kinases）家族的细胞外信号调节激酶（extracellular signal-regulated kinase, ERK）、c-Jun氨基末端激酶（c-Jun N-terminal kinase, JNK）与p38，能够磷酸化并激活可介导增殖与炎症应答的转录因子；而糖皮质激素受体（glucocorticoid receptor, GR）的活化则可抑制细胞生长与炎症反应。本研究证实，ERK与JNK可在体外环境中主要于Ser-246位点对GR进行磷酸化，p38则无此活性。在活体动物体内选择性激活ERK或JNK，均可抑制GR介导的转录激活过程，该效应依赖于JNK对GR Ser-246位点的磷酸化，而非ERK的直接磷酸化作用。综上可见，JNK可通过直接磷酸化GR来抑制其转录激活功能，而ERK则通过间接途径实现该抑制效应。本研究提出，JNK对GR的磷酸化，或ERK对GR辅因子的磷酸化，可为糖皮质激素信号与有丝分裂原或促炎信号发生冲突时，快速抑制GR依赖型基因表达提供潜在的分子机制。