ADENOVIRUS 243R E1A PROTEIN AND CELLULAR TRANSCRIPTION

对人类致癌机制的重要见解已经出现。 来自DNA肿瘤病毒的研究。DNA肿瘤病毒腺病毒 为研究转录事件提供了一个理想的系统 细胞转化。我们研究的长期目标是 了解腺病毒E1a蛋白改变细胞周期的机制 正常的细胞转录程序，从而诱导转化。 在这里，我们主要关注细胞内c-fos的转录调控。 重组腺病毒243R E1A蛋白与基因的功能相互作用 在E1a和细胞转录机制之间。我们以前的 研究发现，E1a的作用与一种重要的 细胞内信号系统，cAMP依赖的蛋白激酶途径。 这种相互作用导致一组基因的激活，这些基因是 参与细胞生长控制和转化。获得的知识 通过研究E1a对细胞转录调控的影响 WIL有助于更好地理解 转型。 1)c-fos激活中涉及的识别交易因素 在E1a和cAMP的作用下，一个22个核苷酸的“E1a-反应元件”(ERE)已经被发现 确定了243R E1a蛋白介导c-fos的激活。 ERE包含转录因子ATF/CREB的结合位点和 YY1。将确定约束该基因的因素，以及E1a的影响 而夏令营对其水平和活动的影响将被确定。 2)ATF/CREB-YY1复合体的结构和功能。YY1实体 与转录因子AFT/CREB家族成员相互作用。 作为研究ATF/CREB-YY1复合体在 ATF/CREB-YY1的活化b E1a、结构/功能分析 将进行互动。DNA结合和转录 还将调查该建筑群的镇压。 3)作为E1a靶点的ATF/CREB-YY1复合体。E1a可与YY1结合， 改变其DNA结合特性。E1a和YY1的相互作用， 并研究了E1a与ATF/CREB-YY1络合物之间的相互作用。实验 将包括对E1A-YY1相互作用的结构/功能分析，如 以及体外和体内结合试验。这些实验将导致 建立了c-fos基因E1a激活的分子基础模型。

Important insights into the mechanisms of human carcinogenesis have come from the study of DNA tumor viruses. The DNA tumor virus adenovirus provides an ideal system for investigating transcriptional events in cellular transformation. The long-term goal of our research is to understnd the mechanism by which the adenovirus E1A protein alters the normal cellular transcriptional program so as to induce transformation. Here, we focus on the transcriptional regulation of the cellular c-fos gene by the adenovirus 243R E1A protein, and the functional interaction between E1A and the cellular transcriptional machinery. Our previous studies have identified a link between the action of E1A and an important intracellular signling system, the cAMP-dependent protein kinase pathway. This interaction results in the activation of a set of genes that are involved in cellular growth control and transformation. Knowledge gained from studying the effects ofE1A on cellular transcriptional regulation wil lead to better understanding of the molecular events involved in transformation. 1) Identifiction transacting factors involved in the activation of c-fos by E1A and cAMP, A 22 nucleotide "E1A-response element" (ERE) has been identified that mediates activation of c-fos by the 243R E1A protein. The ERE contains binding sites for transcription factors ATF/CREB and YY1. Factors tht bind the ERE will be identified, and the effects of E1A and cAMP on their level and activity will be determined. 2) Structure and function of the ATF/CREB-YY1 complex. YY1 physically interacts with members of the AFT/CREB family of transcription factors. As a prelude to investigating the role of the ATF/CREB-YY1 complex in activation b E1A, structure/function analysis of the ATF/CREB-YY1 interaction will be performed. DNA-binding and transcriptional repression by the complex will also be investigated. 3) The ATF/CREB-YY1 complex as a target ofE1A. E1A can bind to YY1 and alter its DNA-binding properties. The interaction between E1A and YY1, and between E1A and the ATF/CREB-YY1 complex will e studied. Experiments will include structure/function analysis of the E1A-YY1 interaction, as well as in itro and in vivo binding assays. These experiments will lead to a model for the molecular basis of E1a activation of thec-fos gene.