p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein 1
p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein 1
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DOI：
10.1210/me.2004-0075
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发表时间：
2006-05-01
影响因子：
--
通讯作者：
Burow, ME
中科院分区：
文献类型：
--
作者：
Frigo, DE;Basu, A;Burow, ME
核激素受体，如雌激素受体（ER），由特定的激酶信号通路调节。在这里，我们证明，p38 MAPK刺激ER α和ER β介导的转录在MCF-7乳腺癌，石川子宫内膜腺癌，和人胚肾293细胞。使用p38抑制剂RWJ 67657抑制这种增强作用，阻断了雌激素介导的转录和增殖。激活的ER部分通过募集p160类共激活因子来促进基因表达。因为没有直接的p38磷酸化位点已被确定在ER α或β，我们假设，p38可以靶向p160类辅激活剂。我们首次使用药理学和分子技术表明，p160辅激活剂糖皮质激素受体相互作用蛋白1（GRIP 1）是磷酸化和增强的p38 MAPK信号级联在体外和体内。S736被鉴定为p38诱导GRIP 1转录激活的必要位点。GRIP 1的C端也被证明含有p38反应区。综上所述，这些结果表明，p38刺激ER介导的转录通过靶向GRIP 1辅激活因子。
Nuclear hormone receptors, such as the estrogen receptors (ERs), are regulated by specific kinase signaling pathways. Here, we demonstrate that the p38 MAPK stimulates both ER alpha- and ER beta-mediated transcription in MCF-7 breast carcinoma, Ishikawa endometrial adenocarcinoma, and human embryonic kidney 293 cells. Inhibition of this potentiation using the p38 inhibitor, RWJ67657, blocked estrogen-mediated transcription and proliferation. Activated ERs promote gene expression in part through the recruitment of the p160 class of coactivators. Because no direct p38 phosphorylation sites have been determined on either ER alpha or beta, we hypothesized that p38 could target the p160 class of coactivators. We show for the first time using pharmacological and molecular techniques that the p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) is phosphorylated and potentiated by the p38 MAPK signaling cascade in vitro and in vivo. S736 was identified as a necessary site for p38 induction of GRIP1 transcriptional activation. The C terminus of GRIP1 was also demonstrated to contain a p38-responsive region. Taken together, these results indicate that p38 stimulates ER-mediated transcription by targeting the GRIP1 coactivator.