REGULATION OF THE TYPE II TGF -B- RECEPTOR

描述：(改编自调查人员的摘要) 人们普遍认为，转化生长因子-β-1的缺失 受体(转化生长因子-β-受体)在肿瘤发生中起重要作用。 功能性转化生长因子-β受体由几种基因产物组成，包括两种 基本信号成分，I型转化生长因子-β受体和II型 转化生长因子-β受体(TbetaR-II)。在几个肿瘤细胞失效的情况下 在RNA或蛋白质水平表达TbetaR-II基因，没有明显的 该基因编码区的结构突变一直是 观察到的。这表明该基因启动子区域的缺陷 TbetaR-II基因和/或在转录调控机制中的作用 TbetaR-II基因在其异常表达中起关键作用 肿瘤。 因此，里兹诺博士认为重要的是要了解 TbetaR-II基因受调控。在试图理解为什么会这样之前 基因在肿瘤细胞中异常表达，重要的是 了解这种基因是如何正常调控的。胚胎性癌(EC) 细胞非常适合实现这一目标，因为 这些细胞的分化导致转化生长因子-β-受体的启动。 了解TbetaR-II基因是如何调控的努力表明 EC细胞分化导致转录激活 这种基因的基因。基于对人类基因启动子区域的研究 TbetaR-II基因，出现了两种假说。首先，抄写 TbetaR-II基因的影响显著，至少有两个 积极的监管区域和两个消极的监管区域。第二，抄写 因子复合体NF-Y，它与一种负性调节因子结合 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 这与邻近的积极监管因素捆绑在一起。为了测试这些 假设，提出了四个具体目标：1)确定 转录因子相互作用以调节 TbetaR-II基因转录，2)分离TbetaR-II基因启动子区 小鼠TbetaR-II基因并精确定位 调控元件，3)识别结合的转录因子 TbetaR-II基因的调节元件，以及4)决定 EC细胞分化改变细胞染色质结构 TbetaR-II基因与转录因子与关键基因的结合 监管要素。里兹诺博士认为，总的来说，这些研究将 不仅有助于确定TbetaR-II基因是如何正常调控的， 但它们也将为理解为什么会这样做提供基础。 基因在肿瘤中异常表达。

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.