Epidermal growth factor-dependent phosphorylation and ubiquitinylation of MAGE-11 regulates its interaction with the androgen receptor
Epidermal growth factor-dependent phosphorylation and ubiquitinylation of MAGE-11 regulates its interaction with the androgen receptor
复制标题
DOI：
10.1128/mcb.01672-07
复制
发表时间：
2008-03-01
影响因子：
5.3
通讯作者：
Wilson, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Bai, Suxia;Wilson, Elizabeth M.
雄激素受体（AR）是一种配体激活的转录因子，在雄激素依赖性基因调节过程中与共调节蛋白相互作用。黑色素瘤抗原基因蛋白 11 (MAGE-11) 是一种 AR 共调节子，可特异性结合 AR NH2 末端 FXXLF 基序并调节 AR NH2 和羧基末端 N/C 相互作用以增加 AR 转录活性。在这里，我们证明表皮生长因子 (EGF) 信号通过 MAGE-11 的翻译后修饰增加雄激素依赖性 AR 转录活性。双氢睾酮存在下的 EGF 通过 MAGE-11 Thr-360 位点特异性磷酸化以及 Lys-240 和 Lys-245 位点泛素化来稳定 AR-MAGE 复合物。 MAGE-11 的时间依赖性 EGF 诱导的 AR 转录活性增加是通过与 AR 和 MAGE-11 周转增加相关的 AR 激活功能 1 和 2 介导的。结果揭示了生长因子信号传导通过 AR 特异性共调节蛋白的共价修饰增加 AR 转录活性的动态机制。整个 MAGE 基因家族中 MAGE-11 磷酸化和泛素化位点的序列保守性表明这组癌症睾丸抗原具有共同的调节机制。
The androgen receptor (AR) is a ligand-activated transcription factor that interacts with coregulatory proteins during androgen-dependent gene regulation. Melanoma antigen gene protein 11 (MAGE-11) is an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif and modulates the AR NH2- and carboxyl-terminal N/C interaction to increase AR transcriptional activity. Here we demonstrate that epidermal growth factor (EGF) signaling increases androgen-dependent AR transcriptional activity through the post-translational modification of MAGE-11. EGF in the presence of dihydrotestosterone stabilizes the AR-MAGE complex through the site-specific phosphorylation of MAGE-11 at Thr-360 and ubiquitinylation at Lys-240 and Lys-245. The time-dependent EGF-induced increase in AR transcriptional activity by MAGE-11 is mediated through AR activation functions 1 and 2 in association with the increased turnover of AR and MAGE-11. The results reveal a dynamic mechanism whereby growth factor signaling increases AR transcriptional activity through the covalent modification of an AR-specific coregulatory protein. Sequence conservation of the MAGE-11 phosphorylation and ubiquitinylation sites throughout the MAGE gene family suggests common regulatory mechanisms for this group of cancer-testis antigens.