Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Cancer Res. 2012 Jun 1;72(11):2714-9. doi: 10.1158/0008-5472.CAN-11-3773. Epub 2012 May 2.
The E3 ubiquitin ligase Smurf2 mediates ubiquitination and degradation of several protein targets involved in tumorigenesis and induces senescence in human cells. However, the functional role of Smurf2 in tumorigenesis has not been fully evaluated. In this study, we generated a mouse model of Smurf2 deficiency to characterize the function of this E3 ligase in tumorigenesis. Smurf2 deficiency attenuated p16 expression and impaired the senescence response of primary mouse embryonic fibroblasts. In support of a functional role in controlling cancer, Smurf2 deficiency increased the susceptibility of mice to spontaneous tumorigenesis, most notably B-cell lymphoma. At a premalignant stage of tumorigenesis, we documented a defective senescence response in the spleens of Smurf2-deficient mice, consistent with a mechanistic link between impaired senescence regulation and increased tumorigenesis. Taken together, our findings offer the genetic evidence of an important tumor suppressor function for Smurf2.
E3 泛素连接酶 Smurf2 介导泛素化和降解几种参与肿瘤发生的蛋白靶标，并诱导人细胞衰老。然而，Smurf2 在肿瘤发生中的功能作用尚未得到充分评估。在这项研究中，我们生成了 Smurf2 缺陷的小鼠模型，以表征这种 E3 连接酶在肿瘤发生中的功能。Smurf2 缺陷减弱了 p16 的表达并损害了原代小鼠胚胎成纤维细胞的衰老反应。支持在控制癌症方面的功能作用，Smurf2 缺陷增加了小鼠对自发性肿瘤发生的易感性，尤其是 B 细胞淋巴瘤。在肿瘤发生的前恶性阶段，我们在 Smurf2 缺陷小鼠的脾脏中记录到衰老反应缺陷，这与衰老调节受损与肿瘤发生增加之间的机制联系一致。总之，我们的研究结果提供了 Smurf2 作为重要肿瘤抑制因子功能的遗传证据。
