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

描述（申请人描述）：肿瘤抑制基因p53是

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.