CLONING AND ANALYSIS OF STEROID RECEPTOR GENES

我们的研究旨在对新的类固醇激素进行表征 受体和类固醇激素受体相关蛋白。SRS 在生长过程中调节类固醇的复杂生物效应， 发育等生理过程。SHR是 通过结合一种特定的类固醇激素而激活。这被激活了 类固醇受体复合体识别特定的DNA序列 在几种情况下，已被证明是增强剂。组合在一起 特定的SHR和类固醇诱导基因位于活性区域 染色质定义了细胞对特定激素的反应。 鉴于人类体内活跃的大量类固醇激素和他们的 在细胞生长、分化和许多其他方面的重要性 在新陈代谢过程中，人们还可以期待一些类固醇 激素受体基因参与代谢性疾病和 肿瘤的发展。这一点得到了最近两项发现的支持。 三种类固醇激素受体的克隆显示出很强的 这些蛋白质之间的同源性，但也显示出类似的高 类固醇激素受体和病毒之间存在同源性 尔巴癌基因产物。一例乙肝病毒DNA的分析 肝细胞癌中的整合部位显示 乙肝病毒的整合将病毒序列放置在细胞旁边 DNA序列(这里称为HBVHC)，它编码DNA结合 类固醇激素受体的结构域。乙型肝炎病毒核心蛋白的表达 基因可能导致了特定的肝细胞癌的发展。这个 HBVHC序列在正常肝脏中不表达。了解更多信息 关于人类中的乙肝病毒-HC基因和erba相关基因，我们有 从人睾丸和胎盘组织中筛选cDNA文库 存在Erba和HBVHC样克隆，并能够分离到 这样的克隆人。我们现在将确定这些元素的主要顺序 基因产品，检查它们的组织和发育表达， 以及它们可能与恶性肿瘤有关。我们还将 确定这些蛋白质是如何发挥作用的，以及正常类固醇是如何 激素受体可以通过突变转化为基因激活剂 具有促进肿瘤的潜力。我们的目标还包括 类固醇中其他新成员的分离和鉴定 激素受体基因家族。拟议的研究将加强 我们对这类重要调控蛋白的了解 以及它们如何参与正常的细胞调节和肿瘤 发展。

Our research aims at the characterization of new steroid hormone receptors and steroid hormone receptor-related proteins. SHRs mediate the complex biological effects of steroid during growth, development, and other physiological processes. An SHR is activated by binding a specific steroid hormone. This activated steroid-receptor complex recognizes specific DNA sequences which in several cases have been shown to be enhancers. The combination of specific SHRs and steroid-inducible genes located on active chromatin defines the response of a cell to a specific hormone. Given the numerous steroid hormones active in the human and their importance in cell growth, differentiation, and many other metabolic processes, one can also expect a number of steroid hormone receptor genes to be involved in metabolic diseases and tumor development. This is supported by two recent findings. cloning of three steroid hormone receptors revealed a strong homology amongst these proteins but also showed that similarly high homology exists between steroid hormone receptors and the viral erbA oncogene product. Analysis of a hepatitis B virus (HBV) DNA integration site in a hepatocellular carcinoma (HCC) showed that the HBV integration places the viral sequence next to a cellular DNA sequence (called here HBV-HC) which codes for a DNA-binding domain of a steroid hormone receptor. Expression of the HBV-HC gene could have led to the development of the particular HCC. The HBV-HC sequence is not expressed in normal liver. To learn more about the HBV-HC gene and erbA-related genes in the human, we have screened human cDNA libraries from testis and placenta for the presence of erbA and HBV-HC-like clones and were able to isolate such clones. We will now determine the primary sequence of these gene products, examine their tissue and developmental expression, and their possible involvement in malignancies. We will also determine how these proteins function and how a normal steroid hormone receptor can be converted by mutation into a gene activator with tumor-promoting potential. Our goals also include the isolation and characterization of other new members of the steroid hormone receptor gene family. The proposed studies will enhance our knowledge about this important class of regulatory proteins and how they are involved in normal cell regulation and in tumor development.