Imprinted PEG3 domain at 19q13.4 and carcinogenesis

描述（由申请人提供）：本提案旨在确定 父系表达基因PEG 3在卵巢癌中的作用， 在人类19q13.4上定义其他可能参与 致癌作用初步数据表明，PEG 3是显着 下调，并且PEG3启动子CpG岛是高甲基化的。 卵巢肿瘤来自卵巢肿瘤的DNA的亚硫酸氢盐测序将用于 确定PEG 3启动子区域超甲基化的频率。存在 至少三种选择性剪接的PEG 3同种型， 并且以组织依赖性方式父系表达。其中两种亚型 编码不同的锌指蛋白，其共享上游外显子， 锌指结构域。预测第三同种型编码截短的 在组织中与其他PEG 3同种型一起表达的蛋白质， 心脏和胎盘的显著例外，表明一个重要的 组织特异性功能使用PEG 3缺陷的瞬时转染测定 卵巢癌细胞系将被用来确定三个影响， 同种型对细胞生长和凋亡的影响，这两种功能以前被认为是 鼠标Peg3这些研究将有助于阐明人类PEG3 同种型在控制细胞生长，并可能进一步有助于 卵巢癌的潜在诊断和治疗靶点。

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.