Tulane Brain Institute, Tulane University, 200 Flower Hall, New Orleans, LA, 70118, USA; Neuroscience Program, Tulane University, 200 Flower Hall, New Orleans, LA, 70118, USA.
Tulane Brain Institute, Tulane University, 200 Flower Hall, New Orleans, LA, 70118, USA; Neuroscience Program, Tulane University, 200 Flower Hall, New Orleans, LA, 70118, USA; Department of Psychology, Tulane University, 2007 Percival Stern Hall, New Orleans, LA, 70118, USA.
Mol Cell Endocrinol. 2019 Jun 15;490:68-79. doi: 10.1016/j.mce.2019.04.007. Epub 2019 Apr 13.
Non-canonical mechanisms of estrogen receptor activation may continue to support women's cognitive health long after cessation of ovarian function. These mechanisms of estrogen receptor activation may include ligand-dependent actions via locally synthesized neuroestrogens and ligand-independent actions via growth factor-dependent activation of intracellular kinase cascades. We tested the hypothesis that ligand-dependent and ligand-independent mechanisms interact to activate nuclear estrogen receptors in the Neuro-2A neuroblastoma cell line in the absence of exogenous estrogens. Transcriptional output of estrogen receptors was measured following treatment with insulin-like growth factor-1 (IGF-1) in the presence of specific inhibitors for mitogen-activated protein kinase (MAPK), phosphoinositde-3 kinase (PI3K), and neuroestrogen synthesis. Results indicate that IGF-1-dependent activation of nuclear estrogen receptors is mediated by MAPK, is opposed PI3K, and requires concomitant endogenous neuroestrogen synthesis. We conclude that both cellular signaling context and endogenous ligand availability are important modulators of ligand-independent nuclear estrogen receptor activation.
非经典的雌激素受体激活机制可能会在卵巢功能停止后很长一段时间内继续支持女性的认知健康。这些雌激素受体激活机制可能包括通过局部合成的神经雌激素的配体依赖性作用，以及通过生长因子依赖性细胞内激酶级联的激活的配体非依赖性作用。我们测试了这样一个假设，即在没有外源性雌激素的情况下，配体依赖性和非依赖性机制在Neuro-2A 神经母细胞瘤细胞系中相互作用以激活核雌激素受体。在存在丝裂原活化蛋白激酶（MAPK）、磷酸肌醇-3 激酶（PI3K）和神经雌激素合成的特定抑制剂的情况下，用胰岛素样生长因子-1（IGF-1）处理后，测量雌激素受体的转录产物。结果表明，IGF-1 依赖性核雌激素受体的激活是由 MAPK 介导的，与 PI3K 相反，并且需要伴随的内源性神经雌激素合成。我们得出结论，细胞信号转导环境和内源性配体的可用性都是配体非依赖性核雌激素受体激活的重要调节剂。
