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

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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.