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首页> 外文学位 >Regulation of gene transcription by estrogen receptors alpha and beta: DNA binding, tethering, and coregulatory protein recruitment.
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Regulation of gene transcription by estrogen receptors alpha and beta: DNA binding, tethering, and coregulatory protein recruitment.

机译：雌激素受体α和β对基因转录的调节：DNA结合，系链和共调节蛋白募集。

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摘要

Estrogen is a hormone of critical importance in regulating the development, growth, and maintenance of reproductive tissues. The effects of estrogen are mediated through interaction of the estrogen receptor (ER) with estrogen response elements (EREs) in target genes. Because the ER-ERE interaction plays a crucial role in gene expression, there has been great interest in understanding how this interaction leads to changes in transcription. The work detailed in this study demonstrates that ERalpha and ERbeta differ greatly in their abilities to activate transcription.; To determine whether receptor-induced changes in DNA structure are related to transactivation, the abilities of ERalpha and ERbeta to activate transcription and induce distortion and bending in DNA were compared. We have now shown that although both receptors interact with an ERE, only ERalpha is able to induce a directed change in DNA conformation, and this ERalpha-mediated change in DNA conformation enhances transcription. A number of estrogen-responsive genes, including the human progesterone receptor (PR) gene, contain no identifiable ERE. ERalpha is able to interact with DNA-bound transcription factors to induce gene transcription through a tethering mechanism. We have identified a region in the PR gene that contains two Sp1 sites and conferred estrogen responsiveness to a heterologous promoter in an estrogen and ERalpha-dependent manner. This region and three Sp1- or AP-1 site-containing regions of the PR gene were examined for ability to be activated by ERalpha or ERbeta in the presence of seven ligands in mammary, uterine, and bone cell lines. ERalpha was a more potent activator of transcription than ERbeta, and AP-1 sites were less transcriptionally active than Sp1 sites. These ERalpha and ERbeta-mediated changes in transcription require the recruitment of coregulatory proteins. We have recently identified interaction between a protein disulfide isomerase and ERalpha that results in enhancement of ERalpha-DNA interaction and ER-mediated transcription.; Combining various cis-elements and coregulatory proteins to regulate gene expression may allow for differential expression of the gene under different cell environments and physiological conditions. These studies will advance our understanding of the complex mechanisms by which ERalpha is able to regulate gene expression.
机译：雌激素是调节生殖组织发育，生长和维持的至关重要的激素。雌激素的作用是通过雌激素受体（ER）与靶基因中的雌激素反应元件（ERE）相互作用而介导的。因为ER-ERE相互作用在基因表达中起着至关重要的作用，所以人们对理解这种相互作用如何导致转录变化的兴趣很大。这项研究中详述的工作表明，ERalpha和ERbeta在激活转录的能力上有很大差异。为了确定受体诱导的DNA结构变化是否与反式激活相关，比较了ERalpha和ERbeta激活转录并诱导DNA变形和弯曲的能力。现在我们已经表明，尽管两个受体都与ERE相互作用，但是只有ERalpha能够诱导DNA构象的定向改变，而这种ERalpha介导的DNA构象改变会增强转录。许多雌激素反应性基因，包括人类孕激素受体（PR）基因，都不含可识别的ERE。 ERalpha能够与DNA结合的转录因子相互作用，通过束缚机制诱导基因转录。我们已经确定了PR基因中的一个区域，该区域包含两个Sp1位点，并以雌激素和ERalpha依赖性方式赋予雌激素对异源启动子的响应性。在乳腺，子宫和骨细胞系中存在七个配体的情况下，检查了PR基因的这个区域和三个Sp1-或AP-1位点的区域被ERalpha或ERbeta激活的能力。 ERalpha是比ERbeta更有效的转录激活因子，AP-1位点的转录活性低于Sp1位点。这些ERalpha和ERbeta介导的转录变化需要募集共调节蛋白。我们最近发现了蛋白质二硫键异构酶与ERalpha之间的相互作用，从而增强了ERalpha-DNA相互作用和ER介导的转录。结合各种顺式元件和核心调节蛋白来调节基因表达可以允许基因在不同细胞环境和生理条件下的差异表达。这些研究将增进我们对ERalpha调节基因表达的复杂机制的理解。

著录项

  • 作者

    Schultz, Jennifer Rae.;

  • 作者单位

    University of Illinois at Urbana-Champaign.;

  • 授予单位 University of Illinois at Urbana-Champaign.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 139 p.
  • 总页数 139
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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