Buckwalter Tara L F, Venkateswaran Anjli, Lavender Marc, La Perle Krista M D, Cho Je-Yoel, Robinson Michael L, Jhiang Sissy M
Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, OH 43210, USA.
Oncogene. 2002 Nov 21;21(53):8166-72. doi: 10.1038/sj.onc.1205938.
RET/PTC1 is a rearranged form of the RET proto-oncogene detected in human papillary thyroid carcinomas. We previously showed that thyroid-targeted expression of RET/PTC1 leads to thyroid tumor formation in Tg-PTC1 transgenic mice. Signal transduction pathways mediated by phosphotyrosine 294, 404, or 451 in RET/PTC1 have been shown to be critical for RET-induced transforming activity in vitro. To investigate the contribution of these signaling pathways in RET/PTC1-induced thyroid tumor formation in vivo, we generated and characterized transgenic mice expressing thyroid-targeted RET/PTC1 mutants carrying a site-directed mutation changing tyrosine (Y) to phenylalanine (F) at the residue 294, 404, or 451. In contrast to the 100% tumor formation rate in Tg-PTC1 transgenic mice, tumor formation rates were significantly decreased in Tg-PTC1-Y294F (6%), Tg-PTC1-Y404F (41%), and Tg-PTC1-Y451F (30%) transgenic mice. This indicates that signaling pathways mediated by pY294, pY404, and pY451 do play a role in RET/PTC1-induced tumor formation. However, as tumors are still able to form in some mice within these three mutant transgenic groups, it indicates that none of the signaling pathways mediated by pY294, pY404, or pY451, are solely essential for RET/PTC1-induced tumor formation.
RET/PTC1是在人类甲状腺乳头状癌中检测到的RET原癌基因的重排形式。我们之前表明，在Tg-PTC1转基因小鼠中，甲状腺靶向性表达RET/PTC1会导致甲状腺肿瘤形成。已证明RET/PTC1中由磷酸酪氨酸294、404或451介导的信号转导通路对于RET在体外诱导的转化活性至关重要。为了研究这些信号通路在RET/PTC1诱导的体内甲状腺肿瘤形成中的作用，我们构建并鉴定了表达甲状腺靶向性RET/PTC1突变体的转基因小鼠，这些突变体在第294、404或451位残基处携带将酪氨酸（Y）突变为苯丙氨酸（F）的定点突变。与Tg-PTC1转基因小鼠100%的肿瘤形成率相比，Tg-PTC1-Y294F（6%）、Tg-PTC1-Y404F（41%）和Tg-PTC1-Y451F（30%）转基因小鼠的肿瘤形成率显著降低。这表明由pY294、pY404和pY451介导的信号通路确实在RET/PTC1诱导的肿瘤形成中发挥作用。然而，由于在这三个突变转基因组中的一些小鼠中仍能形成肿瘤，这表明由pY294、pY404或pY451介导的信号通路中没有一个对于RET/PTC1诱导的肿瘤形成是唯一必需的。
