Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen Receptor α Turnover and Functional Activity via the SCFSkp2 Proteasomal Complex
Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen Receptor α Turnover and Functional Activity via the SCFSkp2 Proteasomal Complex
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DOI：
10.1128/mcb.06561-11
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发表时间：
2012-05-01
影响因子：
5.3
通讯作者：
Katzenellenbogen, Benita S.
中科院分区：
文献类型：
--
作者：
Bhatt, Shweta;Xiao, Zhen;Katzenellenbogen, Benita S.
核激素受体雌激素受体α (ER α)在靶细胞中介导雌激素的作用，是乳腺癌细胞基因表达和增殖程序的主要调节因子。乳腺癌细胞中ER α的存在对内分泌治疗的有效性至关重要，其缺失是内分泌不敏感乳腺肿瘤的标志。然而，调控细胞内质网α水平的分子机制尚不完全清楚。我们的研究结果揭示了一种独特的细胞通路，涉及p38丝裂原活化蛋白激酶（p38MAPK）介导的ER α Ser-294磷酸化，该磷酸化指定其被SCFSkp2蛋白酶体复合物翻转。在乳腺癌细胞系和人类肿瘤中，我们一致观察到ER α与Skp2或活性p38MAPK呈反比关系。Skp2对ER α的调控依赖于细胞周期阶段，对于通过ER α促进雌二醇的有丝分裂作用至关重要。有趣的是，通过敲低Skp2或抑制p38MAPK，我们恢复了ER α阴性乳腺癌细胞的功能ER α蛋白水平，并通过雌激素和抗雌激素控制了基因表达和增殖。我们的研究结果强调了在一些内分泌不敏感的ER α阴性乳腺癌中恢复ER α和对内分泌治疗的反应性的新途径。
The nuclear hormone receptor estrogen receptor alpha (ER alpha) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ER alpha in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ER alpha are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK) -mediated phosphorylation of ER alpha at Ser-294 that specifies its turnover by the SCFSkp2 proteasome complex. Consistently, we observed an inverse relationship between ER alpha and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ER alpha regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ER alpha. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ER alpha protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ER alpha-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ER alpha and the responsiveness to endocrine therapy in some endocrine-insensitive ER alpha-negative breast cancers.