Control of Myc-induced tumorigenesis by the ubiquitin-proteasome system: The role of the Trim33 ubiquitin ligase

我研究的主要重点是了解泛素-蛋白酶体系统的改变如何促进肿瘤的发生。作为一个模型系统，我研究Myc癌蛋白的调控，Myc癌蛋白是一种在广泛的人类癌症中激活的转录因子。泛素介导的Myc降解在正常细胞中是有效和快速的，但在肿瘤中经常被致癌突变阻断，导致Myc蛋白的积累。例如，在伯基特淋巴瘤中发现了Myc的稳定突变，在卵巢癌、乳腺癌和结肠癌中发现了编码Fbw7的基因突变，Fbw7是一种针对Myc降解的泛素连接酶。我们最近证明了一种泛素特异性蛋白酶Usp28与Fbw7结合并使Myc去泛素化。Usp28是肿瘤细胞系中Myc稳定性所必需的，并且在人类结直肠癌和乳腺癌中过表达。目前，我们正在生成Usp28的条件敲除模型，该模型将评估该蛋白在发育和体内平衡以及myc诱导的肿瘤发生中的作用。此外，我们正在阐明控制Fbw7-Usp28通路的上游信号，以及该信号在肿瘤发生过程中如何受到影响。我们的数据表明，pi3k依赖性的Fbw7磷酸化对于其与Usp28的关联和Myc的稳定至关重要。最后，我的工作揭示了Myc和β- Trcp泛素连接酶之间的机制新颖和意想不到的联系。因此，我在分子水平上研究β- Trcp如何影响Myc功能，特别是Myc诱导的肿瘤发生。

The primary focus of my research is to understand how alterations in the ubiquitin-proteasome system contribute to tumorigenesis. As a model system, I study the regulation of the Myc oncoprotein, a transcription factor activated in a wide spectrum of human cancers. Ubiquitin-mediated degradation of Myc, efficient and rapid in normal cells, is frequently blocked in tumors by oncogenic mutations, leading to accumulation of the Myc protein. For instance, stabilizing mutations in Myc are found in Burkitt’s lymphoma, and mutations in the gene encoding Fbw7, a ubiquitin ligase that targets Myc for degradation, occur in ovarian, breast and colon cancers. We have recently demonstrated that a ubiquitin-specific protease, Usp28, associates with Fbw7 and deubiquinates Myc. Usp28 is required for Myc stability in tumor cell lines and is overexpessed in human colorectal and breast cancer. Currently we are generating a conditional knockout model for Usp28, which will evaluate the role of this protein in development and homeostasis, and in Myc-induced tumorigenesis. Further, we are elucidating upstream signals that control the Fbw7-Usp28 pathway and how this signaling is affected during tumorigenesis. Our data suggest that PI3K-dependent phosphorylation of Fbw7 is essential for its association with Usp28 and stabilization of Myc. Finally, my work has revealed a mechanistically novel and unexpected link between Myc and the β- Trcp ubiquitin ligase. I am therefore investigating at the molecular level how β- Trcp affects Myc function and, in particular, Myc-induced tumorigenesis.