ESTROGEN CONTROL OF UTERINE GROWTH AND CELL DIVISION

我们的目标是了解细胞增殖的调节， 子宫和其他器官的所有雌激素，天然和合成。 直到 雌激素和抗雌激素的作用， 激素、药物或内分泌干扰物， 主要被认为是2组分模型：雌激素受体（ER） 和配体。 这项工作将分析响应方面的3- 组成部分：ER，配体和激素反应单位（HRU）， 是雌激素反应元件（ERE）加上相关因素。 ERE 不同的雌激素反应基因的HRU是不同的，我们的 假设是HRU因此可以通过以下方式选择性地调节基因表达： ER-配体复合物以及与其他信号传导途径的交叉作用。 我们 将确定（1）具有不同HRU的基因是否被选择性调节 内源性和环境雌激素，（2）如果抗雌激素 选择性地阻断具有不同HRU的基因的表达，以及（3）如果 不同的HRU选择性地受到非ER信号通路的影响。 的 待研究的基因直接受雌激素调节，大多数含有 已知的。 大鼠子宫内源性基因的体内研究和 荧光素酶转基因，+或-ERE，在转基因小鼠中将确保 影响发生在真实的生理环境中。 内源性研究 M基因-7人乳腺癌细胞和用人乳腺癌细胞转染 而老鼠的调节序列将更精确地定义 负责观察到的基因表达模式， ER与不同ERE的结合将指示ER-ERE亲和力如何贡献 基因调控的模式。 实际上，这一建议要求， 不同的雌激素（例如，内源性vs环境性，不同 内源性雌激素等）选择性地改变基因表达，如果 任何一种雌激素对雌激素受体的不同水平的占有产生不同的 激素调节的基因产物的比率。 因为基因表达是 调节细胞生长和功能的基础，答案很重要 了解内源性雌激素的生殖生理学; 药理学的答案是重要的，以了解生殖 内源性雌激素的生理学;抗雌激素的药理学， 用于激素替代和避孕的药物;以及 内分泌干扰物

Our objective is to understand the regulation of cell proliferation in the uterus and other organs by all estrogens, natural and synthetic. Until now the actions of estrogens and antiestrogens whether endogenous hormones, drugs, or endocrine disruptors in the environment, have been considered primarily as a 2-component model: the estrogen receptor (ER) and the ligand. This work will analyze responses in terms of 3- components: the ER, the ligand, and the hormone response unit (HRU), which is the estrogen response element (ERE) plus associated factors. The EREs and HRUs of different estrogen responsive genes are different, and our hypothesis is that HRUs could thus selectively regulate gene expression by the ER-ligand complex and by cross talk with other signaling pathways. We will determine (1) if genes with different HRUs are selectively regulated by endogenous and environmental estrogens, (2) if antiestrogens selectively block expression of genes with different HRUs, and (3) if different HRUs are selectively affected by non-ER signaling pathways. The genes to be studied are directly regulated by estrogens and most contain known EREs. In vivo studies of endogenous genes in the rat uterus and a luciferase transgene, + or- an ERE, in transgenic mice will insure that effects occur in a true physiological context. Studies of endogenous genes in M-7 human breast cancer cells and transfections with human and rat regulatory sequences will more precisely define the factors responsible for the observed patterns of gene expression, and studies of ER binding to different EREs will indicate how ER-ERE affinity contributes to patterns of gene regulation. In practical terms this proposal asks if different estrogens (e.g., endogenous vs environmental, different endogenous estrogens, etc.) selectively change gene expression, and if different levels of ER occupancy by any single estrogen produce different ratios of hormone regulated gene products. As gene expression is the basis for regulating cell growth and function, the answers are important to understand the reproductive physiology of endogenous estrogens; the pharmacology of answers are important to understand the reproductive physiology of endogenous estrogens; the pharmacology of antiestrogens and drugs used for hormone replacement and contraception; and the toxicity of endocrine disruptors.