MUTATION-INDEPENDENT ALTERATION OF P53 IN BREAST CANCER

乳腺癌中 P53 的突变独立改变

• 批准号: 2101413
• 负责人: UTE Martha MOLL
• 金额: $ 10.3万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-15 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101413
• 关键词: DNA binding protein; breast neoplasms; cell cycle; cell nucleus; cytoplasm; gene expression; gene mutation; genetic models; genetically modified animals; immunocytochemistry; immunofluorescence technique; immunoprecipitation; laboratory mouse; neoplastic cell; nucleic acid sequence; phosphorylation; polymerase chain reaction; temperature sensitive mutant; tissue /cell culture; tumor suppressor genes

The normal p53 gene product plays a key role in blocking cell division. Many human cancers, e.g., of the colon, breast, lung and brain, retain only a mutant allele of the gene and lose the other copy altogether. When wild type p53 is reintroduced into cancer cells, their rapid cell division stops completely. We now think that most cancer cells are under a strong selection pressure to circumvent the growth suppressing functions of the normal p53 protein one way or another. However, in breast cancer, only about 30% of the cases carry inactivating p53 mutations. My work has produced strong evidence that breast cancer can utilize an alternative pathway to eliminate p53 function: wild type p53 is inactivated on the level of the protein by excluding it from the cell nucleus, its site of action, and accumulating it in the cytoplasm. This is intriguing, since it might be important for the understanding of other cancers with a relatively low incidence of p53 mutations (ovarian, prostate, thyroid, certain lung cancers, etc.). The specific aims of this proposal are to use biochemical and genetic techniques to determine the importance and elucidate the molecular mechanism of this pathway. The specific aims involve: a) enlarging the database of the original observation, b) establishing in vitro models to be used in experimental manipulations, c) testing if chemical modifications of the p53 protein and/or an abnormal 'anchor' protein exist to account for the exclusion, and d) gaining insight into p53 regulation of normal breast cells by examining a similar type of p53 exclusion that occurs during pregnancy and lactation. The design of future cancer therapies will use an approach that reintroduces essential elements that the normal cell uses to control cell division. Since p53 will be at the forefront of this effort, it is crucial that we understand the various mechanisms by which cancer cells inactivate this protein.

正常的p53基因产物在阻断细胞分裂中起关键作用。 许多人类癌症，例如结肠，乳房，肺和大脑，保留 只有该基因的突变等位基因，完全失去了其他副本。什么时候 野生型p53被重新引入癌细胞，其快速细胞分裂 完全停止。我们现在认为大多数癌细胞都处于强大状态 选择压力以规避生长抑制功能 正常的p53蛋白一种或另一种方式。 但是，在乳腺癌中，只有大约30％的病例失活 p53突变。我的工作已经有很大的证据表明乳腺癌可以 利用替代途径消除p53功能：野生型p53是 通过将蛋白质排除在细胞中，在蛋白质的水平上灭活 细胞核，其作用部位，并将其积聚在细胞质中。这是 有趣的是，因为这对于理解其他人可能很重要 p53突变发生率相对较低的癌症（卵巢，， 前列腺，甲状腺，某些肺癌等）。这个特定的目的 建议是使用生化和遗传技术来确定 重要性并阐明该途径的分子机制。这 具体目的涉及：a）放大原始数据库 观察，b）建立用于实验的体外模型 操纵，c）测试是否对p53蛋白进行化学修饰 和/或存在异常的“锚定”蛋白来解释排除， d）通过了解对正常乳腺细胞调节正常乳腺细胞的洞察力 检查在怀孕期间发生的类似类型的p53排除和 哺乳。 未来癌症疗法的设计将使用一种方法 重新引入正常单元用来控制细胞的基本元素 分配。由于p53将处于这一努力的最前沿，因此至关重要 我们了解癌细胞灭活的各种机制 该蛋白质。