Effects of estrogen on global gene expression: identification of novel targets of estrogen action.
Effects of estrogen on global gene expression: identification of novel targets of estrogen action.
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发表时间：
2000-11
期刊：
影响因子：
11.2
通讯作者：
A. Charpentier;A. Bednarek;R. Daniel;K. A. Hawkins;K. J. Laflin;S. Gaddis;M. Macleod;Claudio Marcelo Aldaz
中科院分区：
文献类型：
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作者：
A. Charpentier;A. Bednarek;R. Daniel;K. A. Hawkins;K. J. Laflin;S. Gaddis;M. Macleod;Claudio Marcelo Aldaz
性激素雌激素在疾病和生理过程中所起的重要作用已经得到了很好的证明。然而，这种激素激发其许多正常和病理作用的机制尚不清楚。为了鉴定受雌激素作用调控或与雌激素作用相关的已知和未知基因，我们对暴露于这种激素后的雌激素反应性乳腺癌细胞的基因表达进行了系列分析。我们检查了大约190，000个mRNA转录本，并监测了12，550个基因的表达行为。观察到绝大多数这些转录物的表达水平在17 β雌二醇（E2）处理后保持恒定。只有大约0.4%的基因在E2处理后3小时表现出>或=3倍的表达增加。我们克隆了5个新基因（E2 IG 1 -5），观察到这些基因在激素治疗中上调。这些最高度诱导的转录，E2 IG 1，似乎是一个新的小热休克蛋白家族的成员。E2 IG 4基因是富含亮氨酸重复序列蛋白大家族的新成员。在结构和结构域同源性的基础上，该基因似乎是在细胞外环境中分泌的良好候选者，因此，可能在乳腺组织重塑和/或上皮-基质相互作用中发挥作用。还鉴定了几个在细胞周期进程调节中具有潜在作用的有趣基因的表达增加，包括Pescadillo和伴侣蛋白CCT 2。两个假定的旁分泌/自分泌因子在乳腺癌细胞生长的调节中具有潜在的重要性，被鉴定为被E2高度上调：斯钙素2，一种钙/磷酸盐稳态激素;和胡萝卜素-β B，一种TGF-β样因子。有趣的是，我们还确定E2 IG 1和斯钙素2仅在雌激素受体阳性乳腺癌细胞系中过表达，因此它们有可能作为乳腺癌生物标志物。这些数据提供了E2对人类E2反应细胞转录程序诱导的变化的全面看法，并且还确定了新的和以前未被怀疑的基因靶点，其表达受这种激素的影响。
The important role played by the sex hormone estrogen in disease and physiological processes has been well documented. However, the mechanisms by which this hormone elicits many of its normal as well as pathological effects are unclear. To identify both known and unknown genes that are regulated by or associated with estrogen action, we performed serial analysis of gene expression on estrogen-responsive breast cancer cells after exposure to this hormone. We examined approximately 190,000 mRNA transcripts and monitored the expression behavior of 12,550 genes. Expression levels for the vast majority of those transcripts were observed to remain constant upon 17beta estradiol (E2) treatment. Only approximately 0.4% of the genes showed an increase in expression of > or =3-fold by 3 h post-E2 treatment. We cloned five novel genes (E2IG1-5), which were observed up-regulated by the hormonal treatment. Of these the most highly induced transcript, E2IG1, appears to be a novel member of the family of small heat shock proteins. The E2IG4 gene is a new member of the large family of leucine-rich repeat-containing proteins. On the basis of architectural and domain homology, this gene appears to be a good candidate for secretion in the extracellular environment and, therefore, may play a role in breast tissue remodeling and/or epithelium-stroma interactions. Several interesting genes with a potential role in the regulation of cell cycle progression were also identified to increase in expression, including Pescadillo and chaperonin CCT2. Two putative paracrine/autocrine factors of potential importance in the regulation of the growth of breast cancer cells were identified to be highly up-regulated by E2: stanniocalcin 2, a calcium/phosphate homeostatic hormone; and inhibin-beta B, a TGF-beta-like factor. Interestingly, we also determined that E2IG1 and stanniocalcin 2 were exclusively overexpressed in estrogen-receptor-positive breast cancer lines, and thus they have the potential to serve as breast cancer biomarkers. This data provides a comprehensive view of the changes induced by E2 on the transcriptional program of human E2-responsive cells, and it also identifies novel and previously unsuspected gene targets whose expression is affected by this hormone.