A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.
A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.
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动力学模型将磷酸化雌激素受体-α (ERα) 确定为乳腺癌 ERα 动力学的关键调节因子。
DOI：
10.1096/fj.14-265637
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Kreeger,PamelaK
中科院分区：
文献类型：
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作者：
Tian,Dan;Solodin,NataliaM;Rajbhandari,Prashant;Bjorklund,Kelsi;Alarid,ElaineT;Kreeger,PamelaK
受体水平是细胞调节对刺激反应的关键机制。雌激素受体-α（ERα）水平影响乳腺癌细胞增殖，并用于预测预后和对内分泌治疗的敏感性。尽管这些信息的临床应用，仍然不清楚不同的细胞过程如何相互作用作为一个系统来控制ERα水平。为了解决这一问题，使用17-β-雌二醇或溶剂对照处理ERα阳性人乳腺癌细胞系（MCF-7）的实验结果来建立ERα调节的质量作用动力学模型。模型分析表明，RNA动力学可以通过磷酸化ERα（pERα）依赖的转录反馈来捕获。实验分析证实pERα-S118与雌激素受体1（estrogen receptor-1，ESR 1）启动子结合，提示pERα对ESR 1的转录具有反馈作用。蛋白质动力学需要一个单独的机制，其中pERα的降解速率是非磷酸化ERα的8.3倍。使用具有两种机制的模型，均方根误差为0.078。该组合模型的敏感性分析确定，虽然多种机制调节ERα水平，但pERα依赖性反馈引起最强的效应。结合起来，我们的计算和实验结果将ERα的磷酸化确定为协调细胞回路以调节ERα水平的关键决策点。Tian，D.，Solodin，N. M.，Rajbhandari，P.，Bjorklund，K.，Alarid，E. T.，克里格峰一个动力学模型将磷酸化雌激素受体-α（ERα）确定为乳腺癌中ERα动力学的关键调节因子。
Receptor levels are a key mechanism by which cells regulate their response to stimuli. The levels of estrogen receptor-α (ERα) impact breast cancer cell proliferation and are used to predict prognosis and sensitivity to endocrine therapy. Despite the clinical application of this information, it remains unclear how different cellular processes interact as a system to control ERα levels. To address this question, experimental results from the ERα-positive human breast cancer cell line (MCF-7) treated with 17-β-estradiol or vehicle control were used to develop a mass-action kinetic model of ERα regulation. Model analysis determined that RNA dynamics could be captured through phosphorylated ERα (pERα)-dependent feedback on transcription. Experimental analysis confirmed that pERα-S118 binds to the estrogen receptor-1 (ESR1) promoter, suggesting that pERα can feedback on ESR1 transcription. Protein dynamics required a separate mechanism in which the degradation rate for pERα was 8.3-fold higher than nonphosphorylated ERα. Using a model with both mechanisms, the root mean square error was 0.078. Sensitivity analysis of this combined model determined that while multiple mechanisms regulate ERα levels, pERα-dependent feedback elicited the strongest effect. Combined, our computational and experimental results identify phosphorylation of ERα as a critical decision point that coordinates the cellular circuitry to regulate ERα levels.—Tian, D., Solodin, N. M., Rajbhandari, P., Bjorklund, K., Alarid, E. T., Kreeger, P. K. A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.