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

泛素蛋白酶体系统控制 Myc 诱导的肿瘤发生：Trim33 泛素连接酶的作用

基本信息

批准号：
164011727
负责人：
Professor Dr. Nikita Popov
金额：
--
依托单位：
Innere Medizin VIII: Klinische Tumorbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/164011727?language=en
关键词：
Control Myc induced tumorigenesis ubiquitin

项目摘要

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.

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发生。作为一个模型系统，我研究了Myc癌蛋白的调节，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降解在正常细胞中有效且快速，在肿瘤中经常被致癌突变阻断，导致Myc蛋白的积累。例如，Myc中的稳定突变在伯基特淋巴瘤中发现，而编码Fbw 7（一种靶向Myc降解的泛素连接酶）的基因中的突变发生在卵巢癌、乳腺癌和结肠癌中。我们最近已经证明，泛素特异性蛋白酶，Usp 28，与Fbw 7和deubiquinates Myc。Usp 28是肿瘤细胞系中Myc稳定性所必需的，并且在人结直肠癌和乳腺癌中过表达。目前，我们正在建立一个Usp 28的条件性敲除模型，该模型将评估该蛋白在发育和稳态中的作用，以及Myc诱导的肿瘤发生。此外，我们正在阐明控制Fbw 7-Usp 28通路的上游信号，以及这种信号在肿瘤发生过程中如何受到影响。我们的数据表明，Fbw 7的PI 3 K依赖性磷酸化对于其与Usp 28的关联和Myc的稳定是必不可少的。最后，我的工作揭示了Myc和β- Trcp泛素连接酶之间的一种机制上的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。