REGULATION OF THE TYPE II TGF -B- RECEPTOR

II 型 TGF -B- 受体的调节

基本信息

批准号：
2724734
负责人：
A. ANGIE RIZZINO
金额：
$ 19.76万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-14 至 2002-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2724734
关键词：
biological signal transduction cell differentiation cell line chromatin gene expression genetic mapping genetic promoter element genetic regulation genetic regulatory element genetic transcription growth factor receptors regulatory gene tissue /cell culture transcription factor transforming growth factors

项目摘要

DESCRIPTION: (adapted from the investigator's abstract) It is widely believed that the loss of transforming growth factor-beta- receptors (TGF-beta- R) contributes significantly to carcinogenesis. Functional TGF-beta-R comprise several gene products, including two essential signaling components, the type I TGF-beta-R and the type II TGF-beta-R (TbetaR-II). In several instances in which tumor cells fail to express the TbetaR-II gene at the RNA or protein level, no apparent structural mutations within the coding region of the gene have been observed. This suggests that defects in the promoter region of the TbetaR-II gene and/or in the mechanisms regulating the transcription of the TbetaR-II gene play key roles in its aberrant expression in certain neoplasms. Thus, Dr. Rizzino feels that it is important to understand how the TbetaR-II gene is regulated. Before attempting to understand why this gene is expressed aberrantly in tumor cells, it is important to understand how this gene is regulated normally. Embryonal carcinoma (EC) cells are well suited to achieving this objective, since the differentiation of these cells leads to the turn on of TGF-beta-R. Efforts to understand how the TbetaR-II gene is regulated have shown that differentiation of EC cells leads to the transcriptional activation of this gene. Based on work with the promoter region of the human TbetaR-II gene, two hypotheses have emerged. First, the transcription of the TbetaR-II gene is influenced significantly by at least two positive and two negative regulatory regions. Second, the transcription factor complex NF-Y, which binds to one of the negative regulatory elements in the gene, reduces the transcription of the TbetaR-II gene by interfering with the binding or function of transcription factors that bind to neighboring positive regulatory elements. To test these hypotheses, four Specific Aims are proposed: 1) determine which transcription factors interact with one another to regulate the transcription of the TbetaR-II gene, 2) isolate the promoter region of the murine TbetaR-II gene and map precisely the location of the regulatory elements, 3) identify the transcription factors that bind to the regulatory elements of the TbetaR-II gene, and 4) determine whether differentiation of EC cells alters the chromatin structure of the TbetaR-II gene and the binding of transcription factors to critical regulatory elements. Together, Dr. Rizzino feels that these studies will not only help determine how the TbetaR-II gene is regulated normally, but they will also provide the groundwork for understanding why this gene is aberrantly expressed in tumors.

描述：（根据调查员的摘要进行了改编）人们普遍认为，转化生长因子 - β- 受体（TGF-β-R）对癌变有显着贡献。功能性TGF-β-R组成了几种基因产物，包括两个必需的信号分量，I型TGF-BETA-R和II型 tgf-beta-r（tbetar-ii）。在肿瘤细胞失败的一些情况下为了在RNA或蛋白质水平上表达TBETAR-II基因基因编码区域内的结构突变已经观察到。这表明在启动子区域的缺陷 TBETAR-II基因和/或在调节转录的机制中 tbetar-II基因在某些异常表达中起关键作用肿瘤。因此，Rizzino博士认为了解如何了解 TBETAR-II基因受调节。在尝试理解为什么基因在肿瘤细胞中异常表达，对了解如何正常调节该基因。胚胎癌（EC）细胞非常适合实现这一目标，因为这些细胞的分化导致TGF-beta-R的打开。了解如何调节TBETAR-II基因的努力已显示 EC细胞的分化导致转录激活这个基因。基于与人类的发起人区域的工作 TBETAR-II基因，出现了两个假设。首先，转录 Tbetar-II基因的基因受到至少两个的影响正和两个负调节区域。第二，转录因子复合物NF-Y，与负调节之一结合基因中的元素减少了tbetar-II基因的转录通过干扰转录因子的结合或功能与邻近的正调节元件结合。测试这些假设，提出了四个具体目标：1）确定哪个转录因子相互作用以调节 tbetar-II基因的转录，2）隔离启动子区域鼠tbetar-ii基因并精确地绘制了调节元素，3）确定与 TBETAR-II基因的调节元素，4）确定是否确定 EC细胞的分化改变了染色质结构 TBETAR-II基因和转录因子与关键的结合监管要素。 Rizzino博士在一起认为这些研究将不仅有助于确定tbetar-II基因正常调节的方式但是他们还将为理解为什么这样做提供基础基因在肿瘤中异常表达。