p38γ Mitogen-activated Protein Kinase (MAPK) Confers Breast Cancer Hormone Sensitivity by Switching Estrogen Receptor (ER) Signaling from Classical to Nonclassical Pathway via Stimulating ER Phosphorylation and c-Jun Transcription*
p38γ Mitogen-activated Protein Kinase (MAPK) Confers Breast Cancer Hormone Sensitivity by Switching Estrogen Receptor (ER) Signaling from Classical to Nonclassical Pathway via Stimulating ER Phosphorylation and c-Jun Transcription*
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DOI：
10.1074/jbc.m112.349357
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发表时间：
2012-03
期刊：
影响因子：
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通讯作者：
Xiaomei Qi;Huiying Zhi;Adrienne Lepp;Phillip Wang;Jian Huang;Z. Basir;C. Chitambar;C. Myers;Guan Chen
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文献类型：
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作者：
Xiaomei Qi;Huiying Zhi;Adrienne Lepp;Phillip Wang;Jian Huang;Z. Basir;C. Chitambar;C. Myers;Guan Chen
背景：ER通过与雌激素反应元件结合并与c-jun相互作用来传递信号。结果：p38γ在Ser-118处使ER磷酸化。这增加了ER-c-jun的结合，促进了AP-1依赖的转录，并增加了乳腺癌激素的敏感性。结论：p38γ通过调节经典和非经典途径之间的ER信号通路增加乳腺癌激素敏感性。意义：调节p38γ活性可能是提高乳腺癌激素敏感性的新途径。雌激素受体(ER)α通过经典的雌激素反应元件(ERE)结合和非经典的(与AP-1位点的c-jun相互作用)途径调节基因表达，从而促进乳腺癌的生长。ER是他莫昔芬等抗雌激素药物的靶点()。然而，经典和非经典ER信号影响激素敏感性的可能性尚不清楚。此外，除了靶ER外，抗雌激素还经常激活几个信号级联反应，而这些“非靶标”信号事件的含义尚未被探索。在这里，我们报道了p38γMAPK被处理选择性地激活。这导致ER在Ser-118处的磷酸化和c-jun转录的刺激，从而将ER信号从经典途径切换到非经典途径，导致激素敏感性增加。出乎意料的是，ER需要Ser-118位的磷酸化才能与p38γ和c-jun结合，从而促进ER从ERE到AP-1启动子位置的重新定位。因此，ER/Ser118的磷酸化可能是p38γ与其抑制剂共同调控ER信号转导的重要机制。
Background: ER signals through binding to estrogen-responsive elements and interacting with c-Jun. Results: p38γ phosphorylates ER at Ser-118. This increases ER-c-Jun binding, promotes AP-1-dependent transcription, and confers breast cancer hormone sensitivity. Conclusion: p38γ increases breast cancer hormone sensitivity by regulating ER signaling between classical and nonclassical pathways. Significance: Regulating p38γ activity may be a new approach to increase breast cancer hormone sensitivity. Estrogen receptor (ER) α promotes breast cancer growth by regulating gene expression through classical estrogen response element (ERE) binding and nonclassical (interaction with c-Jun at AP-1 sites) pathways. ER is the target for anti-estrogens such as tamoxifen (TAM). However, the potential for classical versus nonclassical ER signaling to influence hormone sensitivity is not known. Moreover, anti-estrogens frequently activate several signaling cascades besides the target ER, and the implications of these “off-target” signaling events have not been explored. Here, we report that p38γ MAPK is selectively activated by treatment with TAM. This results in both phosphorylation of ER at Ser-118 and stimulation of c-Jun transcription, thus switching ER signaling from the classical to the nonclassical pathway leading to increased hormone sensitivity. Unexpectedly, phosphorylation at Ser-118 is required for ER to bind both p38γ and c-Jun, thereby promoting ER relocation from ERE to AP-1 promoter sites. Thus, ER/Ser-118 phosphorylation serves as a central mechanism by which p38γ regulates signaling transduction of ER with its inhibitor TAM.