Internal Medicine, Department of Cardiology, Angiology, and Pneumology, Magdeburg University, 39120 Magdeburg, Germany.
Mol Biol Cell. 2010 May 1;21(9):1620-8. doi: 10.1091/mbc.e09-08-0724. Epub 2010 Mar 10.
Estrogens are suggested to play a role in the development and progression of proliferative diseases such as breast cancer. Like other steroid hormone receptors, the estrogen receptor-alpha (ERalpha) is a substrate of protein kinases, and phosphorylation has profound effects on its function and activity. Given the importance of DNA-dependent protein kinase (DNA-PK) for DNA repair, cell cycle progression, and survival, we hypothesized that it modulates ERalpha signaling. Here we show that, upon estrogen stimulation, DNA-PK forms a complex with ERalpha in a breast cancer cell line (MELN). DNA-PK phosphorylates ERalpha at Ser-118. Phosphorylation resulted in stabilization of ERalpha protein as inhibition of DNA-PK resulted in its proteasomal degradation. Activation of DNA-PK by double-strand breaks or its inhibition by siRNA technology demonstrated that estrogen-induced ERalpha activation and cell cycle progression is, at least, partially dependent on DNA-PK.
雌激素被认为在乳腺癌等增殖性疾病的发展和进展中发挥作用。与其他甾体激素受体一样，雌激素受体-α（ERα）是蛋白激酶的底物，磷酸化对其功能和活性有深远的影响。鉴于 DNA 依赖性蛋白激酶（DNA-PK）对 DNA 修复、细胞周期进程和存活的重要性，我们假设它调节 ERα 信号。在这里，我们表明，在雌激素刺激下，DNA-PK 在乳腺癌细胞系（MELN）中与 ERα 形成复合物。DNA-PK 在丝氨酸 118 位点磷酸化 ERα。磷酸化导致 ERα 蛋白的稳定，因为 DNA-PK 的抑制导致其蛋白酶体降解。双链断裂激活 DNA-PK 或 siRNA 技术抑制 DNA-PK 表明，雌激素诱导的 ERα 激活和细胞周期进程至少部分依赖于 DNA-PK。
