ROLES AND REGULATION OF P53

该计划项目的目标是启动一个跨学科和高度协作的计划，研究P53肿瘤抑制蛋白，并将研究结果转化为癌症患者更合理的治疗。这将需要将结构、生化和分子方法的发现与动物模型和对人类肿瘤的分析结合起来。为了了解P53的蛋白分解，Pavletich将进行X射线结晶学研究，以确定P53、E6和E6AP蛋白的复合体的结构。他还将与A.Levine合作，对带有RNA的MDM2进行结构研究，并与C.Prives合作，研究p53与上游DNA损伤反应蛋白激酶的相互作用。Prives将研究在应激信号后使P53磷酸化的蛋白激酶的作用和特性，还将研究P53家族成员p63和p73的特性。PRIVES将与Levine合作研究MDM2的磷酸化，并比较细胞对P53家族成员的下游反应。莱文将研究遗传背景对近交系小鼠p53诱导下游反应的影响，还将研究MDM2对核质关闭的影响。此外，Leine将与Cordon-Cardo合作研究遗传背景对人类癌症患者对癌症治疗反应的影响。S.Lowe将利用小鼠E：-Myc淋巴瘤小鼠模型来评估P53的反应，并确定小鼠中影响其疾病和对癌症治疗反应的遗传决定因素。洛威将与Prives合作，研究癌基因在向p53发出信号中的作用，并将与Cordon-Cardo合作，将已知的影响动物p53反应的基因的发现应用于评估它们在人类肿瘤中的状态。最后，Cordon-Cardo将转化这些研究的结果，以开发具有预测价值的分子标记，最终目标是为个别癌症患者量身定做治疗和管理。因此，该计划的联合PIs将共同努力，积累关于p53的广泛新发现，并将他们的发现用于临床目的。

The goal of this program project are to mount an interdisciplinary and highly collaborative program to study the p53 tumor suppressor protein and to translate findings into more rational treatment of cancer patients. This will require combining findings from structural, biochemical and molecular approaches with animal models and analysis of human tumors. To understand proteolysis of p53 N. Pavletich will perform X-ray crystallography to determine the structure of a complex of p53, E6 and E6AP proteins. He will also work with A. Levine and to perform structural studies on Mdm2 with RNA, and with C. Prives to study the interaction of p53 with upstream DNA damage-responsive protein kinases. C. Prives will study the roles and properties of protein kinases which phosphorylate p53 after stress signals and will also examine the properties of of p53 family members p63 and p73. Prives will collaborative with Levine to study phosphorylation of Mdm2, and to compare downstream responses of cells to p53 family members. A. Levine will examine the impact of genetic background on the downstream response of p53 induction in inbred strains of mice, and will also study nucleo-cytoplasmic shutting by Mdm2. In addition, collaborative studies Leine will work with Cordon-Cardo to study the impact of genetic background on human cancer patients response to cancer therapy. S. Lowe will exploit a mouse E:-Myc lymphoma mouse model to evaluate the p53 response and to identify the genetic determinants in mice which would affect their disease and response to cancer therapy. Lowe will collaborate with Prives to study the role of oncogenes in signaling to p53 and with Cordon-Cardo will apply findings of genes known to affect p53 response in animals to evaluation of their status in human tumors. Finally, Cordon-Cardo will translate findings from these studies in order to development molecular markers with predictive value with the eventual goal of tailoring treatment and management of individual cancer patients. Thus the co-PIs of this program will work together to accumulate a broad spectrum of new discoveries about p53 and to exploit their findings for clinical purposes.