Regulation and Interactions of the p53 Family

p53 家族的调控和相互作用

• 批准号: 7112854
• 负责人: Carol Prives
• 金额: $ 20.84万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112854
• 关键词: DNA; DNA binding protein; bioinformatics; carcinogenesis; cell growth regulation; cell line; enzyme activity; enzyme structure; enzyme substrate; gene mutation; human genetic material tag; intermolecular interaction; neoplasm /cancer genetics; nucleic acid sequence; p53 gene /protein; phosphorylation; protein isoforms; protein kinase; protein protein interaction; protein structure function; small molecule; tumor suppressor genes; tumor suppressor proteins

The p53 gene family although small in number, plays important roles in cells and whole animals. p53 itself is a major tumor suppressor that integrates multiple sources of stress with cellular response including arrest, senescence and apoptosis. The p53 homologues p63 and p73 are critical for development based on the phenotype of mice lacking either of these genes, and they may also contribute to tumor suppression. The goal of this project is to understand how p53 members are regulated by previously identified or newly discovered cellular factors and how they interact with each other and with DNA. Aim 1 of this project will focus on the checkpoint kinases Chk1 and Chk2. It will elucidate the structure and function of Chk2 with respect to novel Chk2 phosphorylation sites, Chk2 substrate specificity and interaction with its substrates such as p53. The finding that both Chk kinases through E2F1 control p73 induction after DNA damage will be pursued to elucidate how E2F stability and activity are targeted by Chk1 and Chk2. Whether and how oncogenes abrogate the ability of Chk2 to affect p53 activity will be determined in collaboration with Scott Lowe. With Carlos Cordon-Cardo the properties of newly identified tumor-related Chk2 mutations will be analyzed. The goal of Aim 2 is to identify and characterize proteins that interact with different isoforms of p63. The possible effect of p63 on newly identified proteins will be tested and conversely the effect of new binding partners on p63 activities will be determined. Aim 3 will consist of experiments examining the interactions of p63 and p73 with mutant p53 and with DNA. First, small molecules that can disrupt the interaction between mutant p53 proteins and p63 or p73 will be identified and the cellular outcome of such compounds will be determined. Second, the optimum DNA binding sequences for p63 and p73 isoforms in vitro and in vivo will be determined, and with Arnold Levine an informatics approach will be taken to identify human genes that may be preferentially regulated by these p53 family members.

p53基因家族虽然数量很小，但在细胞和整个动物中起着重要作用。 p53本身是 一个主要的肿瘤抑制剂，将多种应激源与细胞反应相结合，包括停滞， 衰老和凋亡。 p53同源物p63和p73对于基于开发至关重要 缺乏这些基因的小鼠的表型，它们也可能导致肿瘤抑制。这 该项目的目标是了解p53成员如何被先前确定或新的调节 发现细胞因子以及它们如何相互相互作用以及与DNA相互作用。该项目的目标1将 专注于检查点激酶CHK1和CHK2。它将用 尊重新型CHK2磷酸化位点，CHK2底物特异性以及与其底物的相互作用 例如p53。 DNA损伤后通过E2F1控制P73诱导的两种CHK激酶的发现将 被追捕以阐明CHK1和CHK2如何针对E2F稳定性和活动。是否以及如何 Oncogenes废除了CHK2影响p53活性的能力，将与Scott合作确定 Lowe。使用Carlos Cordon-cardo，新确定的与肿瘤相关的CHK2突变的特性将是 分析。目标2的目的是识别和表征与不同同工型相互作用的蛋白质 p63。 p63对新鉴定的蛋白质的可能影响将进行测试，相反 将确定对P63活动的约束伙伴。 AIM 3将包括研究 p63和p73与突变体p53以及与DNA的相互作用。首先，可以破坏的小分子 将鉴定突变体p53蛋白与p63或p73之间的相互作用，并且这种细胞结局 将确定化合物。其次，p63和p73同工型的最佳DNA结合序列 将确定体外和体内，并使用Arnold Levine采用信息学方法来识别 这些p53家族成员可能优先调节的人类基因。