Estrogen treatment increases bone mass and reduces fat mass but is associated with adverse effects in postmenopausal women. Knowledge regarding tissue‐specific estrogen signaling is important to aid the development of new tissue‐specific treatments. We hypothesized that the posttranslational modification phosphorylation in estrogen receptor alpha (ERα) may modulate ERα activity in a tissue‐dependent manner. Phosphorylation of site S122 in ERα has been shown in vitro to affect ERα activity, but the tissue‐specific role in vivo is unknown. We herein developed and phenotyped a novel mouse model with a point mutation at the phosphorylation site 122 in ERα (S122A). Female S122A mice had increased fat mass and serum insulin levels but unchanged serum sex steroid levels, uterus weight, bone mass, thymus weight, and lymphocyte maturation compared to WT mice. In conclusion, phosphorylation site S122 in ERα has a tissue‐dependent role with an impact specifically on fat mass in female mice. This study is the first to demonstrate in vivo that a phosphorylation site in a transactivation domain in a nuclear steroid receptor modulates the receptor activity in a tissue‐dependent manner.

中文翻译：

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雌激素受体α中的磷酸化位点S122在雌性小鼠中具有组织依赖性作用

雌激素治疗可增加骨量并减少脂肪量，但与绝经后妇女的不良反应有关。关于组织特异性雌激素信号传导的知识对于帮助开发新的组织特异性治疗很重要。我们假设雌激素受体α（ERα）中的翻译后修饰磷酸化可能以组织依赖性方式调节ERα活性。体外研究表明 ERα 中位点 S122 的磷酸化会影响 ERα 活性，但体内组织特异性作用尚不清楚。我们在此开发了一种新型小鼠模型并对其进行了表型分析，该模型在 ERα (S122A) 的磷酸化位点 122 处具有点突变。雌性 S122A 小鼠的脂肪量和血清胰岛素水平增加，但血清性类固醇水平、子宫重量、骨量、胸腺重量、和淋巴细胞成熟与 WT 小鼠相比。总之，ERα 中的磷酸化位点 S122 具有组织依赖性作用，特别是对雌性小鼠的脂肪量有影响。该研究首次在体内证明核类固醇受体反式激活域中的磷酸化位点以组织依赖性方式调节受体活性。