THYROID-SPECIFIC RET/PTC ONCOGENE

RET原癌基因编码一种受体类型的酪氨酸激酶，它 作为神经胶质细胞系受体复合体的信号成分 衍生神经营养因子或神经突触素。在人乳头状甲状腺中 肿瘤(PC)，RET是由不同的躯体排列激活的 基因，产生RET/PTC癌基因。在每种情况下，细胞间的 具有酪氨酸激酶活性的RET结构域与N- 激活基因的末端，能够发生二聚化。我们的长- 学期目标是识别和表征RET/PCR诱导的细胞变化 和信号通路，有助于发育和 前列腺癌的病理特征。我们已经确定了三个独特的、早期的 我们的TG-PTC1转基因小鼠甲状腺细胞的变化， 在甲状腺球蛋白(Tg)调控下表达RET/PTc1的基因 推动者。在目前的提案中，确定了三个具体目标。在……里面 目标1，我们试图确定细胞变化是否是 RET/PTC1通过研究时间和剂量之间的关系 RET/PCT1在甲状腺组织中的表达及细胞变化 转基因小鼠，并在原代培养的猪甲状腺细胞中作为 系统更易于操纵。在目标2中，我们将确定是否 PY294、pY404和pY451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/PTC1诱导具有多种特征的甲状腺肿瘤的必要条件 PC的性能。我们建议对这些基本信号进行初步的表征 通过识别与RET/PTC1和RET/PTC1结合的信号蛋白来实现信号通路 RET/PTC1诱导培养细胞差异表达基因的研究 甲状腺细胞。在目标3中，我们将比较甲状腺的致瘤性、细胞 RET/PTC3与RET/PTC1共同诱导的变化及信号转导途径 阐明RET/PTC3的生物学意义和临床相关性 与RET/PTC1相比。

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.