CONTROL OF P53 TUMOR SUPPRESSOR BY CBP/P300

描述（来自应用程序）：本提案的长期目标是 阐明CBP及其家族成员p300在细胞生长中的功能 和肿瘤发生。CBP和p300是转录共激活因子， 转录输出来自多个信号转导途径。生化 有证据表明CBP/p300是乙酰转移酶， 激活p53肿瘤抑制蛋白，表明CBP/p300在 生长调节与这一想法一致，CBP/p300的失活， 病毒癌蛋白E1 A有助于细胞永生化， 转型人体CBP的单等位基因缺失（即Rubinstein Taybi 综合征）和小鼠导致癌症风险增加，支持 CBP在肿瘤发生中的特定作用。开始解决分子基础 RTS患者的肿瘤易感性，并检查CBP和p300 在生长调节和肿瘤发生中的功能，我们建议表征它们的 与p53的功能相互作用。提出了两个具体目标， 在先前生成的CBP和p300缺陷小鼠和细胞上： 1.确定CBP和/或p300在调节p53活性中的作用 分析CBP/p300介导的乙酰化对p53功能的影响， 体外活性。 2.确定p53-CBP或p53-p300相互作用的功能意义 在细胞永生化、体外转化控制和肿瘤中 在小鼠中形成。 拟议的研究不仅将提供关键的见解的作用， CBP和p300在调节p53的肿瘤抑制活性中， 阐明RTS患者肿瘤易感性的分子基础。通过 揭示了该过程中特定乙酰化事件的重要性， 这项工作也可能为调节p53的治疗方法开辟一条新的途径 通过操纵CBP和/或p300的乙酰转移酶活性来调节活性。 使用p53作为一个模型系统，我们也可以揭示功能上的区别， CBP和p300之间的关系这一发现可能为CBP突变提供了依据。 而不是p300突变导致肿瘤易感性。

DESCRIPTION (from the application): The long-term objective of this proposal is to elucidate the function of CBP and its family member p300 in cellular growth and oncogenesis. CBP and p300 are transcriptional co-activators that modulate transcriptional output from multiple signal transduction pathways. Biochemical evidence indicates that CBP/p300 are acetyltransferases that acetylate and activate the p53 tumor suppressor protein, indicating a role of CBP/p300 in growth regulation. Consistent with this idea, the inactivation of CBP/p300 by viral oncoprotein E1A contributes to cellular immortalization and transformation. Mono-allelic loss of CBP in humans (i.e. Rubinstein Taybi syndrome) and in mice leads to an increased risk of cancers, supporting a specific role for CBP in oncogenesis. To begin to address the molecular basis for the tumor susceptibility in RTS patients and to examine how CBP and p300 function in growth regulation and oncogenesis, we propose to characterize their functional interaction with p53. Two specific aims are proposed to capitalize on previously generated CBP and p300 deficient mice and cells: 1. To establish the role of CBP and/or p300 in modulating the activity of p53 and to analyze the functional impact of CBP/p300 mediated acetylation on p53 activity in vitro. 2. To establish the functional significance of p53-CBP or p53-p300 interaction in cellular immortalization, transformation control in vitro, and tumor formation in mice. The proposed research not only will provide critical insights into the role of CBP and p300 in modulating the tumor suppressor activity of p53, but also elucidate molecular basis for the tumor susceptibility in RTS patients. By uncovering the significance of a specific acetylation event in this process, this work may also open a new avenue of therapeutic approach to modulate p53 activity by manipulating the acetyltransferase activity of CBP and/or p300. Using p53 as a model system, we may also uncover the functional distinction between CBP and p300. Such a finding may provide the basis that CBP mutation but not p300 mutation, leads to tumor susceptibility.