ERK/Ribosomal S6 Kinase (RSK) Signaling Positively Regulates Death Receptor 5 Expression through Co-activation of CHOP and Elk1
ERK/Ribosomal S6 Kinase (RSK) Signaling Positively Regulates Death Receptor 5 Expression through Co-activation of CHOP and Elk1
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DOI：
10.1074/jbc.m110.153775
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发表时间：
2010-12-31
影响因子：
4.8
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
--
作者：
Oh, You-Take;Liu, Xiangguo;Sun, Shi-Yong
死亡受体5（DR 5）是一种含有死亡结构域的跨膜受体，在与其配体结合或过表达时触发细胞凋亡。其表达由某些小分子药物（包括塞来昔布）通过尚未完全阐明的机制诱导。目前的研究揭示了一种新的ERK/核糖体S6激酶（RSK）依赖性机制，主要使用塞来昔布作为DR 5诱导剂调节DR 5表达。基于启动子缺失和突变分析以及siRNA介导的基因沉默结果，C/EBP同源蛋白（CHOP）和Elk 1都是塞来昔布诱导的DR 5表达所必需的。CHOP和Elk 1的共表达对增加DR 5启动子活性和DR 5表达表现出增强的作用，表明CHOP和Elk 1协同调节DR 5表达。由于Elk 1是一种ERK调节蛋白，因此我们发现塞来昔布可增加磷酸化ERK 1/2、RSK 2和Elk 1的水平。用MEK抑制剂或ERK 1/2 siRNA抑制ERK信号传导，或用RSK 2抑制剂或RSK 2 siRNA抑制RSK 2信号传导，可消除塞来昔布和其他药物对DR 5的上调。此外，这些抑制抑制塞来昔布诱导的CHOP上调。因此，ERK/RSK依赖性，CHOP和Elk 1介导的机制是DR 5诱导的关键。此外，塞来昔布以ATF 4依赖性方式增加CHOP启动子活性，并且ATF 4的siRNA介导的阻断消除了CHOP诱导和DR 5上调，表明ATF 4参与塞来昔布诱导的CHOP和DR 5表达。总的来说，我们得出的结论是，塞来昔布等小分子通过激活ERK/RSK信号传导以及随后的Elk 1激活和ATF 4依赖性CHOP诱导来诱导DR 5表达。
Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers apoptosis upon binding to its ligand or when overexpressed. Its expression is induced by certain small molecule drugs, including celecoxib, through mechanisms that have not been fully elucidated. The current study has revealed a novel ERK/ribosomal S6 kinase (RSK)-dependent mechanism that regulates DR5 expression primarily using celecoxib as a DR5 inducer. Both C/EBP homologous protein (CHOP) and Elk1 are required for celecoxib-induced DR5 expression based on promoter deletion and mutation analysis and siRNA-mediated gene silencing results. Co-expression of both CHOP and Elk1 exhibited enhanced effects on increasing DR5 promoter activity and DR5 expression, indicating that CHOP and Elk1 co-operatively regulate DR5 expression. Because Elk1 is an ERK-regulated protein, we accordingly found that celecoxib increased the levels of phosphorylated ERK1/2, RSK2, and Elk1. Inhibition of either ERK signaling with a MEK inhibitor or ERK1/2 siRNA, or RSK2 signaling with an RSK2 inhibitor or RSK2 siRNA abrogated DR5 up-regulation by celecoxib as well as other agents. Moreover, these inhibitions suppressed celecoxib-induced CHOP up-regulation. Thus, ERK/RSK-dependent, CHOP and Elk1-mediated mechanisms are critical for DR5 induction. Additionally, celecoxib increased CHOP promoter activity in an ATF4-dependent manner, and siRNA-mediated blockade of ATF4 abrogated both CHOP induction and DR5 up-regulation, indicating that ATF4 is involved in celecoxib-induced CHOP and DR5 expression. Collectively, we conclude that small molecules such as celecoxib induce DR5 expression through activating ERK/RSK signaling and subsequent Elk1 activation and ATF4-dependent CHOP induction.