Jhiang S M, Cho J Y, Furminger T L, Sagartz J E, Tong Q, Capen C C, Mazzaferri E L
Department of Physiology, Ohio State University, Columbus 43210, USA.
Recent Results Cancer Res. 1998;154:265-70. doi: 10.1007/978-3-642-46870-4_17.
The RET/PTC oncogene, a rearranged form of the RET proto-oncogene, has been found to be associated with human papillary thyroid carcinomas. To investigate whether RET/PTC causes papillary thyroid carcinoma, we generated a transgenic mouse model of papillary thyroid carcinoma with targeted expression of RET/PTC1 in the thyroid gland. Thyroid tumors in these RET/PTC1 transgenic mice are characterized by a slow growth rate, thyroid-stimulating hormone (TSH)-responsive tumor progression, and loss of radioiodide-concentrating activity despite continued expression of thyroglobulin (Tg). The time of tumor onset appears to be dependent on the expression level of RET/PTC1 in these transgenic mice. In high-copy RET/PTC1 transgenic mice, cellular abnormalities, including a slightly increased proliferation rate, aberrant follicle formation, and loss of radioiodide-concentrating activity, can be readily identified at embryological day 18. To identify which signaling pathway or pathways perturbed by RET/PTC1 are essential for RET/PTC1 to induce tumor development, we generated transgenic mice carrying a thyroid-targeted RET/PTC1 triple mutant, which contains tyrosine to phenylalanine mutations at tyrosine residues 294, 404, and 451. Initial characterization of the thyroid glands of these RET/PTC1 triple-mutant transgenic mice showed no change in follicular morphology or radioiodide-concentrating activity. This finding suggests that signaling pathways mediated by one or more of these three phosphotyrosine binding sites are essential for RET/PTC1 to induce thyroid tumor development. Finally, in order to investigate whether tumors induced by RET/PTC3 are more aggressive than those tumors induced by RET/PTC1, we also generated thyroid-targeted RET/PTC3 transgenic mice.
RET/PTC癌基因是RET原癌基因的一种重排形式，已发现其与人类甲状腺乳头状癌相关。为研究RET/PTC是否会引发甲状腺乳头状癌，我们构建了一种甲状腺乳头状癌转基因小鼠模型，使RET/PTC1在甲状腺中靶向表达。这些RET/PTC1转基因小鼠的甲状腺肿瘤具有生长缓慢、促甲状腺激素（TSH）反应性肿瘤进展以及尽管甲状腺球蛋白（Tg）持续表达但放射性碘摄取活性丧失的特征。肿瘤发生时间似乎取决于这些转基因小鼠中RET/PTC1的表达水平。在高拷贝RET/PTC1转基因小鼠中，在胚胎第18天即可轻易识别出细胞异常，包括增殖率略有增加、异常滤泡形成以及放射性碘摄取活性丧失。为确定RET/PTC1扰乱的哪些信号通路对于RET/PTC1诱导肿瘤发展至关重要，我们构建了携带甲状腺靶向RET/PTC1三重突变体的转基因小鼠，该突变体在酪氨酸残基294、404和451处存在酪氨酸到苯丙氨酸的突变。对这些RET/PTC1三重突变转基因小鼠甲状腺的初步表征显示，滤泡形态或放射性碘摄取活性没有变化。这一发现表明，由这三个磷酸酪氨酸结合位点中的一个或多个介导的信号通路对于RET/PTC1诱导甲状腺肿瘤发展至关重要。最后，为研究RET/PTC3诱导的肿瘤是否比RET/PTC1诱导的肿瘤更具侵袭性，我们还构建了甲状腺靶向RET/PTC3转基因小鼠。
