8P22 ALTERATIONS, IN PROSTATE, BREAST AND ESOPHAGEAL CA

8P22 前列腺、乳房和食管 CA 的改变

• 批准号: 6514210
• 负责人: CARLO M CROCE
• 金额: $ 41.78万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-05 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514210
• 关键词: athymic mouse; breast neoplasms; cell line; chromosome deletion; esophagus neoplasm; gene mutation; genetically modified animals; human tissue; laboratory rabbit; neoplasm /cancer genetics; prostate neoplasms; tumor suppressor genes

Deletions at chromosome 8p22 are very frequent in some of the most common human cancers, including those of the prostate, breast and esophagus. During the past five years we have made an effort to clone genes frequently involved in human epithelial tumors and have been able to clone the gene at 3p, FHIT, that is involved in the pathogenesis of some of the most common human cancers, including lung cancer, and is mutated more frequently than the p53 gene in human malignancies. In this application, it is I proposed to identify and characterize the gene at 8p22 that is altered in prostate, breast and esophageal cancer. The PI has already identified a region of 1.5Mb that is frequently involved in loss of heterozygosity at 8p22 in several epithelial malignanciesas well as several genes in this region. Analysis of these genes for mutations and/or altered expression in human epithelial cancers indicated that one of them, Fez1, is altered in epithelial tumors. The Fez1 gene encodes a leucine zipper protein with a domain similar to the DNA binding domain of the camp responsive activating-transcription factor 5. We have also demonstrated that Fez1 interacts with EFgamma. We propose to investigate the role of the Fez1 gene in human cancer and we will: 1) determine whether Fez1 is a classic tumor suppressor gene by introducing it into prostate, breast and esophageal cancer derived cell lines to establish whether the transfected tumor cells fail to form tumors in immunosuppressed mice, 2) clone and sequence genes encoding Fez1 partner proteins to gain information concerning the function of Fez1 3) knock out the Fez1 gene in the mouse to assess the consequences of Fez1 loss of function in the development of tumors and 4) to investigate large panels of prostate, breast and esophageal cancers for the expression of Fez1 to determine whether Fez1 loss of function has prognostic significance. We will also determine whether Fez1 loss of function makes cancer cells more resistant to chemotherapeutic drugs. Finally, we will determine whether FHIT and Fez1 are collaborating tumor suppressor genes

染色体 8p22 的缺失在一些最常见的细胞中非常频繁。 常见的人类癌症，包括前列腺癌、乳腺癌和食道癌。 在过去的五年里我们经常努力克隆基因 参与人类上皮肿瘤并已能够在 3p 处克隆该基因， FHIT，涉及一些最常见的人类疾病的发病机制 癌症，包括肺癌，并且比 p53 突变更频繁 人类恶性肿瘤中的基因。在这个应用程序中，我建议确定 并描述了在前列腺、乳腺癌和乳腺癌中发生改变的 8p22 基因的特征 食道癌。 PI 已经确定了一个 1.5Mb 的区域，即 经常涉及几种上皮细胞中 8p22 杂合性的丢失 恶性肿瘤以及该区域的几个基因。对这些基因的分析 人类上皮癌中的突变和/或表达改变表明 其中一个 Fez1 在上皮性肿瘤中发生了改变。 Fez1基因编码 亮氨酸拉链蛋白，其结构域与 DNA 结合结构域相似 营反应性激活转录因子 5。我们还证明了 Fez1 与 EFgamma 相互作用。我们建议调查该机构的作用 Fez1基因在人类癌症中的作用，我们将：1）确定Fez1是否是经典的 将抑癌基因导入前列腺、乳腺和食道 癌症衍生细胞系以确定转染的肿瘤细胞是否失败 在免疫抑制小鼠中形成肿瘤，2) 克隆编码基因并对其进行测序 Fez1 伴侣蛋白以获得有关 Fez1 功能的信息 3) 敲除小鼠中的 Fez1 基因以评估 Fez1 缺失的后果 4）研究大组的肿瘤发展中的功能 前列腺癌、乳腺癌和食道癌中 Fez1 的表达确定 Fez1功能丧失是否具有预后意义。我们还将 确定 Fez1 功能丧失是否会使癌细胞更具抵抗力 化疗药物。最后，我们将确定FHIT和Fez1是否是 协同抑癌基因