Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression
Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression
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DOI：
10.1016/j.molcel.2006.01.014
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发表时间：
2006-02-17
期刊：
影响因子：
16
通讯作者：
Leitman, DC
中科院分区：
文献类型：
--
作者：
Cvoro, A;Tzagarakis-Foster, C;Leitman, DC
绝经期间雌激素水平的下降与细胞因子产生增加和炎性疾病有关。雌激素通过抑制细胞因子基因，如肿瘤坏死因子-α（TNF α）发挥抗炎作用。雌激素参与转录抑制的机制实际上是未知的。在这里，我们使用染色质免疫沉淀来研究雌激素如何抑制TNF α基因的自诱导。TNF α在TNF α启动子处组装转录激活复合物，其包括c-jun、p50-NF κ B、p65-NF κ B、CBP、Hsp 90和未配体的雌激素受体（ER）。雌激素通过逆转ER α的配体非依赖性激活以及c-jun、NF κ B和CBP对转录的刺激作用来抑制TNF α基因表达。GRIP 1的沉默逆转了雌二醇对TNF α和其他细胞因子基因的抑制，表明GRIP 1是转录抑制所必需的，并且可以作为辅抑制因子。我们的研究表明，ER α是一种TNF α诱导的共激活因子，在雌二醇存在下通过募集GRIP 1而成为一种阻遏物。
The decline in estrogen levels during menopause is associated with increased cytokine production and inflammatory diseases. Estrogens exert anti-inflammatory effects by repressing cytokine genes, such as tumor necrosis factor-alpha (TNF alpha). The mechanisms involved in transcriptional repression by estrogens are virtually unknown. Here, we used chromatin immunoprecipitation to investigate how estrogens repress the autoinduction of the TNF alpha gene. TNF alpha assembled a transcriptional activation complex at the TNF alpha promoter that includes c-jun, p50-NF kappa B, p65-NF kappa B, CBP, Hsp90, and unliganded estrogen receptor (ER). Estradiol repressed TNFa gene expression by reversing the ligand-independent activation by ER alpha and the stimulatory actions of c-jun, NF kappa B, and CBP on transcription. Silencing of GRIP1 reversed the repression of TNF alpha and other cytokine genes by estradiol, demonstrating that GRIP1 is required for transcriptional repression and can act as a corepressor. Our study demonstrates that ER alpha is a TNF alpha-induced coactivator that becomes a repressor in the presence of estradiol by recruiting GRIP1.