P53 AND UV REGULATION OF P53 BINDING PROTEIN BBP/53BP2

描述(申请人描述)：抑癌基因p53是 在超过50%的人类癌症中发生突变，并在 调节细胞对基因毒性应激的反应。因此，它是 对我们理解癌症至关重要的是研究定义的复杂途径 通过与P53相互作用的蛋白质。BBP/53BP2蛋白与野生型P53结合； P53-BBP/53BP2复合体的晶体结构揭示了BBP/53BP2结合 P53上的位点由进化上保守的区域组成，经常突变 癌症。BBP/53BP2在体外也与细胞凋亡调节相互作用 蛋白Bcl2，增强P53介导的转录激活，并阻碍 L L循环级数。然而，BBP/53BP2的调控机制 都是未知的。候选人已经发现了野性(但不是 突变型)P53可抑制BBP/53BP2蛋白表达，但BBP/53BP2 蛋白质在紫外线照射后被诱导。因此，野生型p53是关键 其结合伴侣BBP/53BP2的调节子，该调节是调节的 通过紫外线诱导的DNA损伤。这个项目的长期目标是了解 BBP/53BP2的功能与癌症的关系这样做的目的是 提案是确定BBP/53BP2的表达是如何调控的，以及如何调控的 影响细胞生理学。这项提议的中心假设是 与野生型P53复合的BBP/53BP2蛋白在非应激细胞中被降解 但在紫外线损伤的细胞中不存在，导致BBP/53BP2上调 蛋白质对紫外线辐射的反应。建议进行这项研究的理由 一旦知道了调控BBP/53BP2表达的机制，那么 其与P53和Bcl2相互作用的体内后果可能是 学习。这一假设将通过追求三个具体目标来检验：1)。 确定野生型p53如何下调BBP/53BP2的表达，2)。测定 紫外线如何上调BBP/53BP2的表达，以及3)。确定 BBP/53BP2表达在细胞紫外线辐射反应中的作用这个 拟议的工作具有创新性，因为它利用了BBP/53BP2和P53 可诱导细胞系研究它们相互作用的功能后果 在有或没有细胞损伤的情况下。预计这将是一次 方法将确定P53依赖和紫外线损伤诱导的机制 控制BBP/53BP2。这一点意义重大，因为理解BBP/53BP2 是由P53调控的，紫外线照射将定义新的调控途径 参与细胞对DNA损伤的反应。拟议的培训计划 处于一个动态的研究环境中，拥有广泛的智力和技术 支持。因此，应聘者将获得获得教员的技能 学术内科肿瘤学方面的职位。

DESCRIPTION (Applicant's Description): The tumor suppressor p53 gene is mutated in over 50 percent of human cancers and plays a pivotal role in mediating the cellular responses to genotoxic stress. Therefore, it is critical to our understanding of cancer to study the complex pathways defined by p53-interacting proteins. Bbp/53BP2 protein binds to wild-type p53; the crystal structure of the p53-Bbp/53BP2 complex reveals the Bbp/53BP2 binding site on p53 consists of evolutionarily conserved regions frequently mutated in cancer. Bbp/53BP2 also interacts in vitro with the apoptosis regulating protein Bcl-2, enhances p53-mediated transcriptional activation, and impedes c e l l cycle progression. However, the mechanisms regulating Bbp/53BP2 expression are unknown. The candidate has found that wild-type (but not mutant) p53 can suppress Bbp/53BP2 protein expression, but that Bbp/53BP2 protein is induced following UV-irradiation. Thus, wild-type p53 is a key regulator of its binding partner Bbp/53BP2, and this regulation is modulated by UV-induced DNA-damage. The long-range goal of this project is to understand how the function of Bbp/53BP2 relates to cancer. The objective of this proposal is to determine how Bbp/53BP2 expression is regulated and how this affects cellular physiology. The central hypothesis of this proposal is that Bbp/53BP2 protein complexed to wild-type p53 is degraded in unstressed cells but not in UV-damaged cells, resulting in the upregulation of Bbp/53BP2 protein in response to UV-irradiation. The rationale for the proposed research is that once the mechanisms regulating Bbp/53BP2 expression are known, then the in vivo consequences of its interactions with p53 and Bcl-2 can be studied. The hypothesis will be tested by pursuing three specific aims: 1). Determine how wild-type p53 downregulates Bbp/53BP2 expression, 2). Determine how UV-irradiation upregulates Bbp/53BP2 expression, and 3). Determine the role of Bbp/53BP2 expression in the cellular response to UV-irradiation. The proposed work is innovative because it capitalizes on Bbp/53BP2 and p53 inducible cell lines to study the functional consequences of their interaction in the presence or absence of cellular damage. It is expected that this approach will identify p53-dependent and UV-damage inducible mechanisms controlling Bbp/53BP2. This is significant because understanding how Bbp/53BP2 is modulated by p53 and UV- irradiation will define new regulatory pathways involved in the cellular response to DNA-damage. The proposed training program is in a dynamic research environment with extensive intellectual and technical support. Thus, the candidate will acquire the skills to secure a faculty position in academic medical oncology.