Calcineurin regulates the stability and activity of estrogen receptor α
Calcineurin regulates the stability and activity of estrogen receptor α
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DOI：
10.1073/pnas.2114258118
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发表时间：
2021-11-02
影响因子：
11.1
通讯作者：
Shimada, Midori
中科院分区：
文献类型：
--
作者：
Masaki, Takahiro;Habara, Makoto;Shimada, Midori
雌激素受体α（ER-α）介导雌激素依赖性癌症进展，并在大多数乳腺癌细胞中表达。然而，调节ER-α的细胞丰度和活性的分子机制仍不清楚。我们在这里表明，蛋白磷酸酶钙调磷酸酶调节ER-α的稳定性和活性在人类乳腺癌细胞。钙调神经磷酸酶缺失或抑制通过促进其多聚泛素化和降解下调ER-α的丰度。钙调神经磷酸酶抑制还促进ER-α与E3泛素连接酶E6 AP的结合，并且钙调神经磷酸酶在体外介导ER-α在Ser（294）处的去磷酸化。此外，ER-α（5294 A）突变体更稳定，并激活ER-α靶基因的表达，以更大的程度相比，野生型蛋白，而其与E6 AP和多聚泛素化的相互作用的程度减弱。这些结果表明ER-α在Ser（294）处的磷酸化促进其与E6 AP的结合和随后的降解。还发现钙调神经磷酸酶是雷帕霉素复合物1的机械靶点在Ser（118）处使ER-α磷酸化以及随后响应于β-雌二醇处理而激活ER-α所需的。因此，我们的研究表明，钙调神经磷酸酶通过调节其在Ser 294和Ser的磷酸化来控制ER-α的稳定性和活性（118）。最后，钙调磷酸酶A-α基因（PPP 3CA）的表达与ER-α阳性乳腺癌患者接受他莫昔芬或其他内分泌治疗药物治疗的预后不良相关。因此，钙调神经磷酸酶是开发ER-α阳性乳腺癌疗法的有希望的靶点。
Estrogen receptor alpha (ER-alpha) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-alpha remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-alpha stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-a by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-alpha to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-alpha at Ser(294) in vitro. Moreover, the ER-alpha (5294A) mutant was more stable and activated the expression of ER-alpha target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-alpha at Ser(294) promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-alpha at Ser(118) by mechanistic target of rapamycin complex 1 and the consequent activation of ER-alpha in response to beta-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-alpha by regulating its phosphorylation at Ser 294 and Ser(118) . Finally, the expression of the calcineurin A-alpha gene (PPP3CA) was associated with poor prognosis in ER-alpha-positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-alpha-positive breast cancer.