Han Sang Jun, Tsai Sophia Y, Tsai Ming-Jer, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Endocrinology. 2007 May;148(5):2471-86. doi: 10.1210/en.2006-1561. Epub 2007 Feb 15.
RU486 is an incomplete progesterone receptor (PR) antagonist due to its partial agonist activity. To investigate the tissue-specific effects of RU486 on PR function in an ovariectomized mouse model, we used the progesterone receptor activity indicator mouse and evaluated the key determinants of progesterone-dependent gene activity: PR, coregulators, and kinases. As might be expected, acute RU486 treatment (6 h after injection) reduced PR transcriptional activity in the uterus, compared with vehicle or progesterone (P4) treatments. Chronic RU486 treatment (3 d) had a distinctly different effect on PR-mediated transcription, elevating PR activity in both the uterus and mammary gland, whereas chronic P4 treatment reduced PR activity in both tissues. This elevated uterine PR activity was associated with increased modified forms of PR and total protein levels of steroid receptor coactivator (SRC)-1 without affecting SRC-2 or SRC-3 protein levels. In addition to increased levels of coactivators, chronic RU486 treatment activated the ERK-1/2 and c-Jun N-terminal kinase signaling pathways in the uterus in a manner comparable with P4 treatment. In contrast to our observations in the uterus, chronic RU486 treatment increased modified forms of PR and the SRC-3 protein levels (but not SRC-1 and SRC-2 levels) in luminal epithelial cells of the mammary gland. Chronic RU486 also activated the c-Jun N-terminal kinase, but not ERK-1/2, signaling pathways in mammary luminal epithelial cells. This report suggests that in comparison with chronic natural hormone (P4), a mixed antagonist/agonist (RU486) induces a distinct temporal and spatial pattern of cellular genetic regulators that accompany ligand-specific gene expression.
RU486因其部分激动剂活性而成为一种不完全的孕激素受体（PR）拮抗剂。为了在去卵巢小鼠模型中研究RU486对PR功能的组织特异性影响，我们使用了孕激素受体活性指示小鼠，并评估了孕激素依赖性基因活性的关键决定因素：PR、共调节因子和激酶。正如预期的那样，与溶剂或孕酮（P4）处理相比，急性RU486处理（注射后6小时）降低了子宫中的PR转录活性。慢性RU486处理（3天）对PR介导的转录有明显不同的影响，提高了子宫和乳腺中的PR活性，而慢性P4处理则降低了这两个组织中的PR活性。子宫中这种升高的PR活性与PR修饰形式的增加以及类固醇受体共激活因子（SRC）-1的总蛋白水平升高有关，而不影响SRC-2或SRC-3蛋白水平。除了共激活因子水平增加外，慢性RU486处理以与P4处理相当的方式激活了子宫中的ERK-1/2和c-Jun N端激酶信号通路。与我们在子宫中的观察结果相反，慢性RU486处理增加了乳腺腔上皮细胞中PR的修饰形式和SRC-3蛋白水平（但不包括SRC-1和SRC-2水平）。慢性RU486还激活了乳腺腔上皮细胞中的c-Jun N端激酶，但未激活ERK-1/2信号通路。本报告表明，与慢性天然激素（P4）相比，混合拮抗剂/激动剂（RU486）诱导了伴随配体特异性基因表达的细胞遗传调节因子的独特时空模式。
