p38 mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: Correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211
p38 mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: Correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211
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DOI：
10.1210/me.2004-0528
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发表时间：
2005-06-01
影响因子：
--
通讯作者：
Thompson, EB
中科院分区：
文献类型：
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作者：
Miller, AL;Webb, MS;Thompson, EB
糖皮质激素（GC）通过激活GC受体（GR）诱导淋巴样细胞凋亡。我们已经评估了p38（一种MAPK）在使用合成GCs地塞米松（Dex）或去酰基可替拉唑（DAC）治疗淋巴样细胞凋亡中的作用。高度保守的磷酸化蛋白p38 MAPK通过其苏氨酸180和酪氨酸182残基的特异性磷酸化被激活。我们发现，Dex和DAC刺激p38 MAPK磷酸化，并增加MAPK激酶3的mRNA， MAPK激酶3是p38 MAPK的特异性直接上游激活剂。酶分析证实p38 MAPK活性升高。药理抑制p38 MAPK活性对gc驱动的人和小鼠淋巴样细胞凋亡具有保护作用。相反，抑制MAPKs、ERK和cJun n -末端激酶可促进细胞凋亡。活化的p38 MAPK磷酸化特定的下游靶标。由于GR的磷酸化受到MAPKs的影响，我们在我们的系统中检测了它的磷酸化状态。我们发现人GR的丝氨酸211在体外和细胞内都是p38 MAPK的底物。该位点的丙氨酸突变大大减少了gr驱动基因的转录和凋亡。我们的研究结果清楚地证明了p38 MAPK信号在gc诱导的淋巴样细胞凋亡通路中的作用。
Glucocorticoids (GCs) induce apoptosis in lymphoid cells through activation of the GC receptor (GR). We have evaluated the role of p38, a MAPK, in lymphoid cell apoptosis upon treatment with the synthetic GCs dexamethasone (Dex) or deacylcortivazol (DAC). The highly conserved phosphoprotein p38 MAPK is activated by specific phosphorylation of its threonine180 and tyrosine182 residues. We show that Dex and DAC stimulate p38 MAPK phosphorylation and increase the mRNA of MAPK kinase 3, a specific immediate upstream activator of p38 MAPK. Enzymatic assays confirmed elevated activity of p38 MAPK. Pharmacological inhibition of p38 MAPK activity was protective against GC-driven apoptosis in human and mouse lymphoid cells. In contrast, inhibition of the MAPKs, ERK and cJun N-terminal kinase, enhanced apoptosis. Activated p38 MAPK phosphorylates specific downstream targets. Because phosphorylation of the GR is affected by MAPKs, we examined its phosphorylation state in our system. We found serine 211 of the human GR to be a substrate for p38 MAPK both in vitro and intracellularly. Mutation of this site to alanine greatly diminished GR-driven gene transcription and apoptosis. Our results clearly demonstrate a role for p38 MAPK signaling in the pathway of GC-induced apoptosis of lymphoid cells.