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Molecular mechanisms regulating estradiol production in the rat corpus luteum.

机译：调节大鼠黄体中雌二醇生成的分子机制。

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摘要

Estradiol is required for the survival of the rat corpus luteum (CL) throughout pregnancy and is produced throughout gestation by the CL itself. In early pregnancy, estradiol is produced de novo from progesterone, however during the second half of pregnancy, the CL loses this capability. This is compensated by the fetal placenta, which at this stage begins to secrete androstenedione which the CL can convert to estradiol. The steroidogenic enzymes involved in the production of estradiol by the rat CL have not been characterized, and this study sought to examine the changes occurring at a molecular level which allowed for this change in the mechanism of estradiol biosynthesis.;We found that PRL receptor-associated protein (PRAP), a luteal protein originally cloned in our lab, is a novel isoform of 17betaHSD responsible for the final step of estradiol biosynthesis in the rat CL. Transfection studies in vitro found that the association of PRAP with the PRL receptor allowed PRL to induce the phosphorylation of PRAP on tyrosine residues, and that this involved the tyrosine kinase JAK2. Through RT-PCR, the mRNA expression of PRAP/17betaHSD and P450c17, another enzyme involved in estradiol synthesis, were found to change in the CL during pregnancy, and their differential expression patterns appear to be crucial to the change in estradiol production in the rat CL. The expression of both of these steroidogenic enzymes is regulated by both luteinizing hormone (LH) and estradiol over the course of gestation, as determined by in vivo experiments. We cloned and characterized the PRAP promoter, and demonstrated that two Sp1 binding sites appear to be involved in regulation of its basal expression. In a rat luteal cell line, cAMP, a second messenger utilized by LH in the rat corpus luteum, could inhibit PRAP promoter activity and stimulate P450c17 promoter activity, mimicking the effects of LH on the mRNA expression of these two enzymes in the rat corpus luteum. In EMSA experiments, using control and hCG-treated luteal nuclear extracts, a NF-Y binding site in the PRAP promoter was shown to bind NF-Y in control rats, while it did not bind when treated with hCG. This mechanism was not used by cAMP in the rat luteal cell line, suggesting that LH could inhibit PRAP transcription through two pathways, one involving cAMP and a second which leads to prevention of NF-Y binding to the PRAP promoter.
机译：雌二醇是整个孕期大鼠黄体（CL）生存所必需的，并且在整个妊娠过程中都由雌激素本身产生。在怀孕初期，雌激素是从孕激素重新产生的，但是在怀孕的后半段，CL失去了这种能力。这可以通过胎盘来补偿，胎盘在此阶段开始分泌雄烯二酮，CL可以将其转化为雌二醇。还没有对大鼠CL中参与雌二醇生产的类固醇生成酶进行鉴定，并且本研究试图检查在分子水平上发生的变化，这些变化允许雌二醇生物合成的机制发生这种变化。相关蛋白（PRAP）是一种最初在我们实验室中克隆的黄体蛋白，是一种17betaHSD的新型同工型，负责大鼠CL中雌二醇生物合成的最后一步。体外转染研究发现，PRAP与PRL受体的结合使PRL能够诱导酪氨酸残基上的PRAP磷酸化，这涉及酪氨酸激酶JAK2。通过RT-PCR，发现PRAP / 17betaHSD和另一种参与雌二醇合成的酶P450c17的mRNA表达在妊娠期CL中发生改变，并且它们的差异表达模式似乎对大鼠雌二醇产生的变化至关重要。 CL。这两种类固醇生成酶的表达均受孕过程中黄体生成激素（LH）和雌二醇的调节，这是通过体内实验确定的。我们克隆并鉴定了PRAP启动子，并证明了两个Sp1结合位点似乎参与了其基础表达的调节。在大鼠黄体细胞系中，LH在大鼠黄体中使用的第二个信使cAMP可以抑制PRAP启动子活性并刺激P450c17启动子活性，模仿LH对大鼠黄体中这两种酶的mRNA表达的影响。 。在EMSA实验中，使用对照和hCG处理的黄体核提取物，显示了PRAP启动子中的NF-Y结合位点在对照大鼠中结合NF-Y，而用hCG处理时则不结合。 cAMP在大鼠黄体细胞系中未使用该机制，表明LH可通过两种途径抑制PRAP转录，一种途径涉及cAMP，另一种途径导致防止NF-Y与PRAP启动子结合。

著录项

  • 作者

    Risk, Michael Christopher.;

  • 作者单位

    University of Illinois at Chicago, Health Sciences Center.;

  • 授予单位 University of Illinois at Chicago, Health Sciences Center.;
  • 学科 Health Sciences Obstetrics and Gynecology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 171 p.
  • 总页数 171
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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