MDM2 AND P53 IN TUMOR CELLS

描述（改编自研究者摘要）：长期 这项研究工作的目标是阐明分子机制， 导致mdm 2癌基因的过度表达，并确定 这种过度表达在肿瘤发生途径中的作用。的 mdm 2癌基因具有转化活性， 过表达，并且经常在人肿瘤细胞中扩增。 由mdm 2癌基因编码的蛋白质可以结合并抑制 两个关键的肿瘤抑制蛋白，p53和RB的功能。乔治医生 已经鉴定了许多人类肿瘤细胞系， mdm 2蛋白和稳定的野生型p53蛋白的水平。 这种意料之外的组合可能代表了一种新的情况， 涉及这些基因的转化。新数据还表明， 这些细胞中mdm 2蛋白超过50倍的过表达， 与增强翻译相关。这一机制以前没有 与mdm 2基因表达的调节有关， 代表了一种新的方法，通过这种方法， mdm 2癌基因的激活。调查人员概述了 实验方法，以更好地定义分子和细胞 mdm 2基因的复杂调控机制，以及 因为它在介导细胞转化过程中的作用。 基于对mdm 2和p53表达改变的初步分析， 在这些肿瘤细胞中，已经形成了一个框架，开始 这可能是一种基本的转化途径。为了实现这一目标， 具体目标包括：（1）阐明千年发展目标2的机制 肿瘤细胞中的翻译控制，并确定它是否直接 与异常p53表达相关或依赖于异常p53表达;（2）表征 更全面地描述了mdm 2和mdm 3的生理状态和相互作用， p53基因产物在这些肿瘤细胞中的表达;（3）检验预测， mdm 2在这些肿瘤中的过表达抑制正常RB功能， 有助于改变增殖控制;（4）确定是否 稳定的p53具有改变的细胞定位或转录 活化电位这些研究有望提供新的见解， 细胞转化的机制，并最终导致更多 有效诊断和治疗人类癌症。

DESCRIPTION (adapted from the investigator's abstract): The long-term goals of this research effort are to elucidate the molecular mechanisms leading to the overexpression of the mdm2 oncogene and to define the role that such overexpression plays in pathways of tumorigenesis. The mdm2 oncogene has transforming activity that can be activated by overexpression, and is frequently amplified in human tumor cells. Proteins encoded by the mdm2 oncogene can bind to, and inhibit the function of, two key tumor suppressor proteins, p53 and RB. Dr. George has identified a number of human tumor cell lines that express very high levels of both mdm2 proteins and a stabilized, wild type p53 protein. This unanticipated combination may represent a new scenario of transformation involving these genes. New data also indicate that the more than 50 fold overexpression of the mdm2 proteins in these cells is associated with enhanced translation. This mechanism has not previously been implicated in the regulation of mdm2 gene expression, and it represents a novel means by which the potential transforming activity of the mdm2 oncogene could be activated. The investigator has outlined experimental approaches to better define the molecular and cellular mechanisms governing the complex regulation of the mdm2 gene, as well as its role in mediating the process of cellular transformation. Building on an initial analysis of the altered mdm2 and p53 expression in these tumor cells, a framework has been developed to begin to dissect what may be a fundamental pathway of transformation. Toward that goal, the specific aims include: (1) Elucidate the mechanism of mdm2 translational control in the tumor cells, and determine if it is directly related to, or reliant on, the aberrant p53 expression; (2) Characterize more fully the physiological status, and interactions, of the mdm2 and p53 gene products in these tumor cells; (3) Test the prediction that overexpression of mdm2 in these tumors inhibits normal RB function, contributing to altered proliferation controls; (4) Determine if the stabilized p53 has an altered cellular location or transcriptional activation potential. These studies promise to provide new insights into mechanisms of cellular transformation, and ultimately lead to more effective diagnosis and therapy of human cancers.