Deroo Bonnie J, Hewitt Sylvia C, Peddada Shyamal D, Korach Kenneth S
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Endocrinology. 2004 Dec;145(12):5485-92. doi: 10.1210/en.2004-0471. Epub 2004 Sep 2.
The rodent uterus responds to acute estradiol (E2) treatment with a series of well characterized physiological responses. In a recent screen for genes involved in this response, we found that several genes in the thioredoxin (Txn) pathway were rapidly modified after E2 treatment in the mouse uterus. Txn is a 12-kDa protein with multiple roles in the cell, including protection against oxidative stress and apoptosis, regulation of transcription factor activity, and regulation of cellular proliferation. Txn in combination with Txn reductase (Txnrd) and Txn-interacting protein (Txnip) constitute the mammalian Txn pathway. This pathway exists in multiple locations in the cell, including the cytosol and mitochondria. To analyze the levels of Txn, Txnrd, and Txnip in the uterus, we treated ovariectomized adult mice with a time course of E2 and analyzed mRNA levels by real-time PCR. E2 rapidly decreased the expression of Txnip, but increased the levels of cytosolic Txn1 and Txnrd1 as well as mitochondrial Txn2. Using the ER antagonist, ICI 182,780, and mice lacking functional estrogen receptor alpha (ERalpha), we demonstrate that these E2-mediated changes require ERalpha, but not ERbeta. The repression of Txnip by E2 was also demonstrated in vitro in MCF-7 human breast cancer cells. This repression was blocked by treatment with the histone deacetylase inhibitor, trichostatin A, suggesting that repression by E2 may involve regulation of histone acetylation. We conclude that the rapid E2-mediated activation of the Txn pathway is an important step in the response of the mammalian uterus to estrogen.
啮齿动物的子宫对急性雌二醇（E2）治疗会产生一系列特征明确的生理反应。在最近一次对参与该反应的基因进行的筛选中，我们发现硫氧还蛋白（Txn）途径中的几个基因在小鼠子宫接受E2治疗后会迅速发生改变。Txn是一种12 kDa的蛋白质，在细胞中具有多种作用，包括抵御氧化应激和细胞凋亡、调节转录因子活性以及调节细胞增殖。Txn与硫氧还蛋白还原酶（Txnrd）和Txn相互作用蛋白（Txnip）共同构成哺乳动物的Txn途径。该途径存在于细胞的多个位置，包括细胞质和线粒体。为了分析子宫中Txn、Txnrd和Txnip的水平，我们对去卵巢的成年小鼠进行了不同时间的E2处理，并通过实时PCR分析mRNA水平。E2迅速降低了Txnip的表达，但增加了细胞质Txn1和Txnrd1以及线粒体Txn2的水平。使用雌激素受体拮抗剂ICI 182,780以及缺乏功能性雌激素受体α（ERα）的小鼠，我们证明这些E2介导的变化需要ERα，而不是ERβ。E2对Txnip的抑制作用在体外MCF-7人乳腺癌细胞中也得到了证实。用组蛋白去乙酰化酶抑制剂曲古抑菌素A处理可阻断这种抑制作用，这表明E2的抑制作用可能涉及组蛋白乙酰化的调节。我们得出结论，E2介导的Txn途径的快速激活是哺乳动物子宫对雌激素反应的重要一步。
