CONTROL OF P53 TUMOR SUPPRESSOR BY CBP/P300

描述(来自申请表)：这项建议的长期目标是 阐明CBP及其家族成员p300在细胞生长中的作用 和致癌作用。CBP和p300是转录共激活子，调节 来自多条信号转导途径的转录输出。生化 有证据表明，CBP/p300是乙酰化和乙酰化的乙酰转移酶 激活P53抑癌蛋白，提示CBP/p300在 生长调控。与这一想法一致，CBP/p300的失活 病毒癌蛋白E1a有助于细胞永生化和 转型。人类CBP的单等位基因丢失(即Rubinstein Taybi 综合症)，并在小鼠中导致癌症风险增加，支持 CBP在肿瘤发生中的特殊作用。开始讨论分子基础 对RTS患者肿瘤易感性的影响，并检测CBP和p300如何 在生长调节和肿瘤发生中的作用，我们建议对它们的特征进行描述 与P53的功能相互作用。提出了两个具体的目标来利用 在先前产生的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 并分析CBP/p300介导的乙酰化对p53功能的影响 体外活性。 2.建立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方面 在小鼠体内形成。 这项拟议的研究不仅将提供对 CBP和p300在调控P53抑瘤活性中的作用 阐明RTS患者肿瘤易感性的分子基础。通过 揭示了这一过程中特定乙酰化事件的重要性， 这项工作也可能为调控p53的治疗开辟一条新的途径 通过调控CBP和/或p300的乙酰基转移酶的活性。 以p53作为模型系统，我们也可能揭示出功能上的差异 在CBP和P300之间。这一发现可能为CBP突变提供依据 但不是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.