Signal transducers and activators of transcription as downstream targets of nongenomic estrogen receptor actions
Signal transducers and activators of transcription as downstream targets of nongenomic estrogen receptor actions
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DOI：
10.1210/me.2002-0072
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发表时间：
2002-10-01
影响因子：
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通讯作者：
Sjöberg, M
中科院分区：
文献类型：
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作者：
Björnström, L;Sjöberg, M
17 -雌二醇激活的雌激素受体α (erα)和β (erβ)能够通过细胞质信号转导途径诱导信号转导因子和转录激活因子（Stat）调控的启动子的转录激活。启动子诱导需要Stat5和Stat3，这与er的细胞质亚定位相关，并且独立于完整的辅激活子结合位点和dna结合域。在内皮细胞中，Stat5和Stat3在酪氨酸和丝氨酸残基上响应17 -雌二醇迅速磷酸化，随后诱导核易位。β -雌二醇诱导stat调控启动子的转激活至少需要三种不同的信号转导途径，包括MAPK、src -激酶和磷脂酰肌醇-3-激酶活性。总之，这项工作确定了一个涉及激动剂结合er激活磷酸化级联的新途径，导致靶转录因子的核转录激活。这些发现揭示了开发药物的新靶点，这些药物可以调节非基因组到基因组的er依赖机制。
17beta-Estradiol-activated estrogen receptor alpha (ERalpha) and beta (ERbeta) are able to induce transcriptional activation of signal transducer and activator of transcription (Stat)-regulated promoters via cytoplasmic signal transduction pathways. Stat5 and Stat3 are required for promoter induction, which correlates with cytoplasmic sublocalization of ERs and is independent of intact coactivator binding sites and DNA-binding domains. In endothelial cells, Stat5 and Stat3 are rapidly phosphorylated on both tyrosine and serine residues in response to 17beta-estradiol, and nuclear translocation is subsequently induced. 17beta-Estradiol-induced transactivation of a Stat-regulated promoter requires at least three different signal transduction pathways, including MAPK, Src-kinase, and phosphatidylino-sitol-3-kinase activities. In conclusion, this work identifies a novel pathway involving an agonist-bound ER-activated phosphorylation cascade, resulting in nuclear transcriptional activation of target transcription factors. These findings reveal novel targets for the development of drugs that modulate a nongenomic-to-genomic ER-dependent mechanism.