CLONING AND ANALYSIS OF STEROID RECEPTOR GENES

我们的研究旨在表征新的类固醇激素 受体和类固醇激素受体相关蛋白。 SHRs 在生长过程中介导类固醇的复杂生物学效应， 发育和其他生理过程。 SHR是 通过结合一种特殊的类固醇激素而被激活。 该活化的 类固醇-受体复合物识别特定的DNA序列， 在一些情况下，已经显示出是增强剂。 相结合 特定的SHR和类固醇诱导基因位于活跃的 染色质决定了细胞对特定激素的反应。 考虑到人体内活跃的多种类固醇激素及其 在细胞生长、分化和许多其它方面重要性 代谢过程中，人们也可以期待一些类固醇 激素受体基因参与代谢疾病， 肿瘤发展 最近的两项研究结果支持了这一点。 三种类固醇激素受体的克隆显示出强烈的 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 erbA癌基因产物。 一例B型肝炎病毒DNA的分析 肝细胞癌（HCC）中整合位点显示， HBV整合将病毒序列置于细胞 编码DNA结合的DNA序列（此处称为HBV-HC） 类固醇激素受体的结构域。 HBV-HC的表达 基因可能导致特定HCC的发展。 的 HBV-HC序列在正常肝脏中不表达。 了解更多 关于人类HBV-HC基因和erbA相关基因，我们有 从睾丸和胎盘中筛选人cDNA文库， erbA和HBV-HC样克隆的存在，并能够分离 这样的克隆人。 我们现在将确定这些的主要顺序 基因产物，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 确定这些蛋白质的功能以及正常的类固醇 激素受体可以通过突变转化为基因激活剂 具有促肿瘤的潜力 我们的目标还包括 甾族化合物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 我们对这类重要的调节蛋白的了解 以及它们如何参与正常细胞调节和肿瘤 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.