Functions of an E1A-Associated Cellular Protein

E1A 相关细胞蛋白的功能

基本信息

批准号：
8066180
负责人：
BAYAR THIMMAPAYA
金额：
$ 2.5万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
1998-04-01 至 2010-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The N-terminal region of the adenovirus transforming protein E1A binds to several host proteins whose functions are critical for the cell cycle control. These include p400, p300 and the highly related CBP, Retinoblastoma protein (Rb), and two Rb related proteins p107 and p130. E1A interactions with these host proteins result in profound alterations in cellular growth control, p300/CBP is a coactivator and a histone acetyl transferase that links chromatin remodeling with transcription. The focus of this application is to investigate the roles played by p300 in cell cycle control and to investigate how E1A binding to p300 deregulates the cell cycle related p300 functions. Recently, this laboratory has shown that depletion of p300 in quiescent cells leads to premature G1 exit and upregulation of c-Myc. Conversely, overexpression of p300 in quiescent cells leads to downregulation of c-Myc followed by inhibition of S phase entry. Thus, p300 provides an important function in G1 control of the cell cycle by negatively regulating Myc, and preventing a premature G1 exit. These results provide a molecular basis for the previously documented need for viral oncoproteins such as E1A and SV40 large-T to inactivate the p300 functions during cell transformation. Here, studies are proposed to investigate the mechanism by which p300 negatively regulates c-Myc at the chromatin level. The specific aims include the identification of the domains and activities of p300 that are critical for the negative regulation of Myc, the Myc promoter specific transcription factors and chromatin remodeling proteins that interact with p300 during this negative regulation, and the mechanism of their interactions that results in the repression of the Myc promoter. Finally, studies are proposed to investigate the mechanism by which EIA inactivates p300 functions that leads to Myc upregulation, and how E1A binding to p300 contributes to the G1 exit. p300/CBP is a key regulator of cell proliferation with tumor suppression properties. Therefore, understanding the functions of this protein in cell cycle control, and the mechanism by which viral oncogene products interfere with its functions will be valuable in understanding the p300 mediated growth regulatory pathways.

描述（由申请人提供）：腺病毒转化蛋白E1A的N末端区域与几种宿主蛋白结合，其功能对于细胞周期控制至关重要。其中包括P400，P300和高度相关的CBP，视网膜母细胞瘤蛋白（RB）和两个相关的RB相关蛋白P107和P130。 E1A与这些宿主蛋白的相互作用导致细胞生长控制的深刻改变，p300/cbp是共激活剂和组蛋白乙酰转移酶，将染色质重塑与转录联系起来。该应用的重点是研究P300在细胞周期控制中扮演的角色，并研究E1A与P300的结合如何消除与细胞周期相关的P300功能。最近，该实验室表明，静态细胞中P300的耗竭导致G1的过早出口和C-MYC的上调。相反，静态细胞中p300的过表达导致c-myc的下调，然后抑制S相进入。因此，p300通过负调控MYC并防止过早的G1出口来控制G1对细胞周期的重要功能。这些结果为先前证明的对病毒癌蛋白（例如E1A和SV40）大量T的需求提供了分子基础，以使细胞转化过程中的p300功能失活。在这里，提出了研究以研究p300在染色质水平上调节C-MYC的机制。具体目的包括鉴定p300的域和活动，这对于在这种负调节过程中与p300相互作用的MYC启动子特异性转录因子和染色质重塑蛋白以及其相互作用机制相互作用至关重要，以及导致MYC启动子的抑制作用。最后，提出了研究来研究EIA使P300功能导致MYC上调的机制，以及E1A与P300与P300的结合如何有助于G1出口。 P300/CBP是具有肿瘤抑制特性的细胞增殖的关键调节剂。因此，了解该蛋白在细胞周期控制中的功能以及病毒癌基产品干扰其功能的机制对于理解p300介导的生长调节途径而言有价值。