IKKepsilon 对雌激素受体 α Ser-167 的磷酸化作用及其在乳腺癌中对他莫昔芬耐药性的贡献。
IKKepsilon phosphorylation of estrogen receptor alpha Ser-167 and contribution to tamoxifen resistance in breast cancer.
机构信息
From the Departments of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612.
Departments of Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612.
出版信息
J Biol Chem. 2010 Feb 5;285(6):3676-3684. doi: 10.1074/jbc.M109.078212. Epub 2009 Nov 23.
IKKepsilon has recently been identified as a breast cancer oncogene. Elevated levels of IKKepsilon are associated with cell survival and growth. Here, we show that IKKepsilon interacts with and phosphorylates estrogen receptor alpha (ERalpha) on serine 167 in vitro and in vivo. As a result, IKKepsilon induces ERalpha transactivation activity and enhances ERalpha binding to DNA. Cyclin D1, a major target of ERalpha, is transcriptionally up-regulated by IKKepsilon in a phospho-ERalpha-Ser-167-dependent manner. Further, overexpression of IKKepsilon induces tamoxifen resistance, whereas knockdown of IKKepsilon sensitizes cells to tamoxifen-induced cell death. These data suggest that ERalpha is a bona fide substrate of IKKepsilon and IKKepsilon plays an important role in tamoxifen resistance. Thus, IKKepsilon represents a critical therapeutic target in breast cancer.
IKKepsilon 最近被确定为乳腺癌致癌基因。IKKepsilon 的高水平与细胞存活和生长有关。在这里，我们表明 IKKepsilon 在体外和体内与雌激素受体 alpha (ERalpha)相互作用并使其丝氨酸 167 磷酸化。结果，IKKepsilon 诱导 ERalpha 转录激活活性并增强 ERalpha 与 DNA 的结合。细胞周期蛋白 D1 是 ERalpha 的主要靶标，IKKepsilon 通过依赖于磷酸化 ERalpha-Ser-167 的方式转录上调。此外，过表达 IKKepsilon 诱导他莫昔芬耐药，而敲低 IKKepsilon 则使细胞对他莫昔芬诱导的细胞死亡敏感。这些数据表明 ERalpha 是 IKKepsilon 的真正底物，IKKepsilon 在他莫昔芬耐药中发挥重要作用。因此，IKKepsilon 是乳腺癌的一个关键治疗靶点。
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