Sumoylation of the estrogen receptor α hinge region regulates its transcriptional activity
Sumoylation of the estrogen receptor α hinge region regulates its transcriptional activity
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DOI：
10.1210/me.2005-0042
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发表时间：
2005-11-01
影响因子：
--
通讯作者：
Corbo, L
中科院分区：
文献类型：
--
作者：
Sentis, S;Le Romancer, M;Corbo, L
类固醇激素 17 β-雌二醇（雌激素）主要通过与其受体雌激素受体 α (ER α) 结合，在乳腺正常生理和乳腺癌发展中发挥重要作用。 ER α 是一种核转录因子，经历不同类型的翻译后修饰，即磷酸化、乙酰化和泛素化，调节其转录激活和/或稳定性。在这里，我们将 ER α 确定为完整细胞和体外小泛素样修饰剂 (SUMO)-1 修饰的新靶标。此外，ERα苏酰化严格在激素存在下发生。 SUMO-1 似乎调节 ER α 依赖性转录。使用一系列突变体，我们证明 ER α 在铰链区内的保守赖氨酸残基处被苏酰化。阻止 SUMO 修饰的突变会损害 ER α 诱导的转录，但不会影响 ER α 细胞定位。除了鉴定激活信号转导子和转录激活子的蛋白抑制剂 (PIAS)1 和 PIAS3 作为 ER α 的 E3 连接酶之外，我们还发现 PIAS1 和 PIAS3 以及 Ubc9 独立于其 SUMO-1 缀合活性来调节 ER α 依赖性转录。这些发现将 SUMO 化确定为调节 ER α 依赖性细胞反应的新机制，并提供 SUMO 和雌激素途径之间的联系。
The steroid hormone 17 beta-estradiol ( estrogen) plays a significant role in the normal physiology of the mammary gland and breast cancer development primarily through binding to its receptor, the estrogen receptor alpha (ER alpha). ER alpha is a nuclear transcription factor undergoing different types of post-translational modifications, i.e. phosphorylation, acetylation, and ubiquitination, which regulate its transcriptional activation and/or stability. Here we identify ER alpha as a new target for small ubiquitin-like modifier (SUMO)-1 modification in intact cells and in vitro. Moreover, ER alpha sumoylation occurs strictly in the presence of hormone. SUMO-1 appears to regulate ER alpha-dependent transcription. Using a series of mutants, we demonstrated that ER alpha is sumoylated at conserved lysine residues within the hinge region. Mutations that prevented SUMO modification impaired ER alpha-induced transcription without influencing ER alpha cellular localization. In addition to identifying protein inhibitor of activated signal transducer and activator of transcription (PIAS)1 and PIAS3 as E3 ligases for ER alpha, we also found that PIAS1 and PIAS3, as well as Ubc9, modulated ER alpha-dependent transcription independently from their SUMO-1 conjugation activity. These findings identify sumoylation as a new mechanism modulating ER alpha-dependent cellular response and provide a link between the SUMO and estrogen pathways.