Regulation and Interactions of the p53 Family

p53基因家族虽然数量不多，但在细胞和整个动物中起着重要作用。p53本身 一种主要的肿瘤抑制因子，它将多种应激源与包括停滞在内的细胞反应整合在一起， 衰老和凋亡。p53同源物p63和p73对于基于基因突变的发育至关重要。 这些基因的突变可能导致缺乏这些基因中任一种的小鼠的表型，并且它们也可能有助于肿瘤抑制。的 本项目的目的是了解p53成员是如何被以前确定的或新发现的调控的。 发现了细胞因子以及它们如何相互作用和与DNA相互作用。该项目的目标1将 重点关注检查点激酶Chk 1和Chk 2。它将阐明Chk 2的结构和功能， 关于新的Chk 2磷酸化位点、Chk 2底物特异性和与其底物的相互作用 例如p53。这两种Chk激酶通过E2 F1控制DNA损伤后p73诱导的发现， 进一步阐明E2 F的稳定性和活性如何被Chk 1和Chk 2靶向。是否以及如何 癌基因消除Chk 2影响p53活性的能力将与Scott合作确定 洛与卡洛斯Cordon-Cardo的新鉴定的肿瘤相关的Chk 2突变的性质将是 分析了目的2的目标是鉴定和表征与不同的异构体相互作用的蛋白质， 第63页。将测试p63对新鉴定的蛋白质的可能作用，并且相反地，将测试新的p63对新鉴定的蛋白质的作用。 将确定对p63活性的结合伴侣。目标3将包括检查 p63和p73与突变型p53和DNA的相互作用。首先，小分子可以破坏 突变型p53蛋白和p63或p73之间的相互作用将被鉴定， 将确定化合物。第二，p63和p73同种型的最佳DNA结合序列， 体外和体内将被确定，并与阿诺德莱文的信息学方法将采取识别 人类基因可能优先受这些p53家族成员调控。

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.