Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center, Abilene, Texas.
Hollings Cancer Center, Charleston, South Carolina.
Mol Cancer Res. 2019 Aug;17(8):1639-1651. doi: 10.1158/1541-7786.MCR-18-1292. Epub 2019 May 14.
We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of and that R72 increases the risk for angiomyolipoma. R72 transactivates and better than the proline variant of codon 72 (P72); therefore, the expression of and is increased in angiomyolipoma cells that carry R72. The loss of and within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high and expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways. IMPLICATIONS: This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling.
我们发现，90.3%的血管平滑肌脂肪瘤、淋巴管平滑肌瘤病（LAM）和结节性硬化症（TSC）患者携带 72 密码子精氨酸变异（R72），且 R72 增加了血管平滑肌脂肪瘤的风险。R72 比脯氨酸变异（P72）更能转录激活 和 ；因此，携带 R72 的血管平滑肌脂肪瘤细胞中 和 的表达增加。在小鼠中，巢蛋白表达细胞中缺失 和 导致肾细胞癌（RCC）的发生，其 和 表达水平较高，提示由于小鼠中 p53 缺失和人类 p53 多态性，类似的下游机制导致肿瘤发生。小鼠 或人 R72 的缺失表达通过 Notch 和 Nodal 途径促进肿瘤细胞的上皮间质转化和运动，从而促进肿瘤发生。意义：这项工作揭示了 p53 多态性对 TSC 发病机制的意外贡献，并确定了由这种多态性引起的信号改变作为治疗靶点。我们发现，72 密码子 TP53 多态性通过 Notch 和 Nodal 信号促进 TSC 相关的肿瘤发生。
