Molecular Studies of the p53 Pathway in Human Cancer

项目4：突变型p53和p63亚型在尿路上皮发育和膀胱癌进展中的作用和调控 卡洛斯·科登-卡多，医学博士，博士。 我们小组的累积观察使我们假设，P53和P63调节尿路上皮分化的分子过程与它们在膀胱癌发生和发展中的作用有因果关系。我们的主要目标是确定P53和P63亚型在尿路上皮发育、膀胱癌发生和发展中的关键功能。为此，我们将使用最先进的分子病理学和遗传学方法，利用体外细胞分析和体内小鼠模型，验证在人类正常和肿瘤膀胱组织中的重要发现。具体目标是： 目的#1.尿路上皮发育过程中P53和P63亚型的综合分析。我们发现p63对于尿路上皮的分化是必不可少的，p63基因缺失的小鼠形成了异常的单细胞层尿路上皮。初步资料支持，该层系由

Project 4: Roles and Regulation of Mutant p53 and p63 Isoforms in Urothelial Development and Bladder Cancer Progression Carlos Cordon-Cardo, M.D., Ph.D. Cumulative observations by our group led us to hypothesize that the molecular processes by which p53 and p63 regulate urothelial differentiation are causally linked to their role in bladder tumor initiation and progression. Our main objective is to define the critical functions of p53 and p63-isoforms in urothelial development, bladder cancer initiation and progression. For this purpose, we will use state-ofthe- art molecular pathology and genetic approaches utilizing in vitro cell-based assays and in vivo mouse models, validating significant findings in human normal and tumor bladder tissues. The specific aims are: Aim #1. Comprehensive analysis of p53 and p63-isoforms during urothelial development. We discovered that p63 is essential for urothelial differentiation, and that p63-null mice developed an abnormal mono-cellular layer urothelium. Prelimianry data supports that this layer is constituted of