Imprinted PEG3 domain at 19q13.4 and carcinogenesis

19q13.4 处的印记 PEG3 结构域与致癌作用

• 批准号: 6536074
• 负责人: Susan Kay Murphy
• 金额: $ 4.17万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-26 至 2003-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536074
• 关键词: DNA methylation; apoptosis; gene induction /repression; genetic promoter element; genetic susceptibility; genomic imprinting; molecular cloning; ovary neoplasms; p53 gene /protein; polymerase chain reaction; protein isoforms; tissue /cell culture; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): This proposal is directed at determining the role of the paternally expressed gene, PEG3, in ovarian cancer, and defining other imprinted genes at human 19q13.4 potentially involved in carcinogenesis. Preliminary data indicate that PEG3 is dramatically downregulated, and that the PEG3 promoter CpG island is hypermethylated in ovarian tumors. Bisulfite sequencing of DNA from ovarian tumors will be used to determine the frequency of PEG3 promoter region hypermethylation. There are at least three alternatively spliced PEG3 isoforms that are maternally imprinted and paternally expressed in a tissue-dependent manner. Two of these isoforms encode distinct zinc finger proteins that share upstream exons independent of the zinc finger domains. The third isoform is predicted to encode a truncated protein that is expressed in tissues together with the other PEG3 isoforms with the notable exception of heart and placenta, suggesting an important tissue-specific function. Transient transfection assays using PEG3-deficient ovarian cancer cell lines will be used to determine the influence of the three isoforms on cellular growth and apoptosis, both functions previously ascribed to mouse Peg3. These studies will help clarify the role of the human PEG3 isoforms in the control of cellular growth, and may further contribute potential diagnostic and therapeutic targets for ovarian cancer.

描述(由申请人提供)：本提案旨在确定 父系表达基因Peg3在卵巢癌中的作用 确定人类19q13.4可能参与的其他印记基因 致癌。初步数据表明，PEG3显著地 Peg3启动子CpG岛被高甲基化 卵巢肿瘤。卵巢肿瘤DNA的亚硫酸氢盐测序将用于 测定Peg3启动子区域高甲基化频率。有在 至少三个母系印记的选择性剪接的Peg3亚型 并以组织依赖的方式在父系中表达。其中两种亚型 编码不同的锌指蛋白，这些蛋白共享上游外显子，独立于 锌指结构域。第三种亚型被预测为编码截断的 与其他PEG3亚型一起在组织中表达的蛋白质 心脏和胎盘的显著例外，表明 组织特有的功能。利用PEG3基因缺陷的瞬时转染检测 将用卵巢癌细胞株来确定三者的影响 异构体对细胞生长和凋亡的影响，这两种功能以前都被认为是 传给鼠标Peg3。这些研究将有助于阐明人类PEG3的作用 异构体在控制细胞生长中的作用，并可能进一步有助于 卵巢癌的潜在诊断和治疗靶点。