MDM2 AND P53 IN TUMOR CELLS

描述(改编自调查人员的摘要)：长期 这项研究的目的是阐明分子机制。 导致MDM2癌基因的过度表达，并定义 这种过度表达在肿瘤发生途径中所起的作用。这个 MDM2癌基因具有可被激活的转化活性 高表达，在人类肿瘤细胞中经常被扩增。 MDM2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。乔治博士 已经确定了一些高表达的人类肿瘤细胞系 MDM2蛋白和稳定的野生型P53蛋白的水平。 这种意想不到的组合可能代表着一种新的情况 涉及这些基因的转化。新数据还表明， MDM2蛋白在这些细胞中的过度表达超过50倍 与增强的翻译相关。这一机制以前没有 与MDM2基因表达的调控有关，而且它 代表了一种新的方法，通过这种方法，潜在的转化活动 可以激活MDM2癌基因的一部分。调查员概述了 更好地定义分子和细胞的实验方法 MDM2基因复杂调控机制的研究 因为它在细胞转化过程中起到了中介作用。 建立在对MDM2和P53表达变化的初步分析基础上 在这些肿瘤细胞中，已经形成了一个框架，开始解剖 这可能是一条转变的基本路径。为了实现这个目标， 具体目标包括：(1)阐明MDM2的发病机制 在肿瘤细胞中的翻译控制，并确定它是否直接 与异常的P53表达有关或依赖的；(2)表征 更全面地了解MDM2的生理状态和相互作用 这些肿瘤细胞中的P53基因产物；(3)检验预测 MDM2在这些肿瘤中的过度表达抑制了正常的Rb功能， 有助于改变扩散控制；(4)确定 稳定的p53具有改变的细胞位置或转录 激活潜力。这些研究有望为我们提供新的见解 细胞转化机制，并最终导致更多 人类癌症的有效诊断和治疗。

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.