Experimental Oncology 1, CRO National Cancer Institute, Aviano 33081, Italy.
Cancer Cell. 2012 Sep 11;22(3):404-15. doi: 10.1016/j.ccr.2012.08.003.
Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates its MDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.
扭蛋白通过影响不同的调控途径，被证明有助于癌症的发生和发展，但它们的作用机制尚不清楚。通过研究扭蛋白在肉瘤中的作用，我们发现 Twist1 作为一种机制替代 TP53 突变和 MDM2 过表达，在间充质肿瘤中使 p53 失活。我们提供的证据表明，Twist1 通过 Twist 盒与 p53 C 端结合。这种相互作用阻碍了 p53 的关键翻译后修饰，并促进了它与 MDM2 的降解。我们的研究表明存在一种扭蛋白失活的 p53 盒密码，并提供了靶向扭蛋白盒：p53 相互作用可能为癌症治疗提供额外途径的原理证明。
