Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation
Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation
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DOI：
10.1128/mcb.22.16.5835-5845.2002
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发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Bai, W
中科院分区：
文献类型：
--
作者：
Lee, H;Bai, W
雌激素受体是磷酸化蛋白，可被配体、激酶激活剂或磷酸酶抑制剂激活。我们前期研究发现p38丝裂原活化蛋白激酶参与雌激素和MEKK1对雌激素受体的激活。在这里，我们报道了雌激素在子宫内膜腺癌细胞中依赖雌激素受体的p38激活，以及通过p38介导的雌激素受体α的体外和体内磷酸化。鉴定磷酸化位点为苏氨酸-311 (Thr(311))，位于激素结合结构域的螺旋1。苏氨酸-311突变为丙氨酸不影响雌激素与受体的结合，但破坏了其与共激活因子的相互作用。p38活性的抑制或该位点的突变抑制了雌激素诱导的受体核定位以及雌激素和MEKK1对其的转录激活。一种特殊的化学抑制剂抑制p38信号通路阻断了雌激素调节内源性基因表达和子宫内膜癌细胞生长的生物活性。我们的研究证实了天然配体诱导的雌激素受体磷酸化在雌激素受体的细胞分布中的作用，并对雌激素在子宫内膜癌细胞中的促生长活性有重要贡献。
Estrogen receptors are phosphoproteins which can be activated by ligands, kinase activators, or phosphatase inhibitors. Our previous study showed that p38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and MEKK1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (Thr(311)), located in helix 1 of the hormone-binding domain. The mutation of threonine-311 to alanine did not affect estrogen binding of the receptor but compromised its interaction with coactivators. Suppression of p38 activity or mutation of the site inhibited the estrogen-induced receptor nuclear localization as well as its transcriptional activation by estrogens and MEKK1. The inhibition of the p38 signal pathway by a specific chemical inhibitor blocked the biological activities of estrogens in regulating endogenous gene expression as well as endometrial cancer cell growth. Our studies demonstrate the role of estrogen receptor phosphorylation induced by the natural ligand in estrogen receptor's cellular distribution and its significant contribution to the growth-stimulating activity of estrogens in endometrial cancer cells.