THYROID-SPECIFIC RET/PTC ONCOGENE

甲状腺特异性 RET/PTC 癌基因

• 批准号: 6124496
• 负责人: Sissy M Jhiang
• 金额: $ 22.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124496
• 关键词: biological signal transduction; cell proliferation; cellular pathology; embryo /fetus cell /tissue; gene expression; genetically modified animals; in situ hybridization; laboratory mouse; neoplasm /cancer genetics; neoplastic process; neoplastic transformation; northern blottings; oncogenes; polymerase chain reaction; protein tyrosine kinase; protooncogene; thyroid gland; thyroid neoplasm; tissue /cell culture; western blottings

The RET proto-oncogene encodes a receptor-type tyrosine kinase, which serve as a signaling component for the receptor complex of glial cell-line derived neurotrophic factor or neurturin. In human papillary thyroid carcinoma (PC), RET is activated by somatic arrangements with different genes, generating RET/PTC oncogenes. In each case, the intercellular domain of RET, which has tyrosine kinase activity, is fused to the N- terminus of the activating gene that is capable of dimerization. Our long- term goal is to identify and characterize RET/PCR-induced cellular changes and signaling pathways that contribute to the development and the pathological properties of PC. We have identified three distinctive, early cellular changes in the thyroid glands of our Tg-PTC1 transgenic mice, which express RET/PTC1 under the control of the thyroglobulin (Tg) promoter. In the current proposal, three specific aims are identified. In Aim 1, we seek to determine whether cellular changes are direct effects of RET/PTC1 by investigating the temporal and dosage relationships between RET/PCT1 expression and these cellular changes in the thyroid glands of Tg-PTC1 transgenic mice, and in primary cultured porcine thyrocytes as a system more amenable to manipulation. In Aim 2, we will determine whether pY294, pY404, and pY451-mediated signaling pathways are responsible for these distinctive cellular changes, and which of these pathways are essential for RET/PTC1 to induce thyroid tumors with many characteristics of PC. We propose to initially characterize these essential signaling pathways by identifying the signaling proteins that bind to RET/PTC1 and the differentially expressed genes induced by RET/PTC1 in cultured thyrocytes. In Aim 3, we will compared thyroid tumorigenicity, cellular changes, and signaling pathways induced by RET/PTC3 with RET/PTC1 to address the biological significance and the clinical relevance of RET/PTC3 compared to RET/PTC1.

RET原癌基因编码受体型酪氨酸激酶， 作为神经胶质细胞系受体复合物的信号成分 衍生的神经营养因子或neurturin。人甲状腺乳头状 在癌症（PC）中，RET通过具有不同的 基因，产生RET/PTC癌基因。在每种情况下， 具有酪氨酸激酶活性的RET结构域与N- 能够二聚化的激活基因的末端。我们长久以来- 长期目标是鉴定和表征RET/PCR诱导的细胞变化 和信号通路，有助于发展和 PC的病理特性。我们已经确定了三个不同的，早期的 我们的Tg-PTC 1转基因小鼠甲状腺的细胞变化， 在甲状腺球蛋白（Tg）的控制下表达RET/PTC 1 启动子在本提案中，确定了三个具体目标。在 目的1，我们试图确定细胞变化是否是 RET/PTC 1通过研究时间和剂量之间的关系 RET/PCT 1表达和这些细胞变化在甲状腺中的作用， Tg-PTC 1转基因小鼠，并在原代培养的猪甲状腺细胞中作为对照。 系统更易于操作。在目标2中，我们将确定 pY 294、pY 404和pY 451介导的信号通路负责 这些独特的细胞变化，以及这些途径中的哪些是 RET/PTC 1诱导具有多种特征的甲状腺肿瘤的必要性 的PC。我们建议首先描述这些基本信号 通过识别与RET/PTC 1结合的信号蛋白， RET/PTC 1诱导的细胞差异表达基因 甲状腺细胞在目标3中，我们将比较甲状腺致瘤性、细胞 RET/PTC 3和RET/PTC 1诱导的变化和信号通路， 阐述RET/PTC 3的生物学意义和临床相关性 与RET/PTC 1相比。