Ubiquitin-mediated protein degradation as a mechanism to control the DNA replication and DNA damage checkpoints in the mammalian cell cycle

• Antragsteller: Professor Dr. Florian Bassermann
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2009
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 25618406

The ubiquitin pathway plays a central role in the regulation of cell growth and cell proliferation by controlling the abundance of key cell cycle proteins. Increasing evidence indicates that unscheduled proteolysis of many cell cycle regulators contributes significantly to tumorigenesis and is indeed found in many types of human cancers, for example colon and renal cell cancer and non hodgkin lymphomas. Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib, an inhibitor of the 26S proteasome. Thus, further work in this area holds great promise toward the understanding and treatment of a wide range of cancers. The laboratory of Dr. Pagano at the NYU Cancer Center has significantly contributed to the understanding of ubiquitin mediated proteolysis and generated fundamental insights into the two major ubiquitin ligases in control of the mammallian cell cycle: The SCF (Skp1 Cul1 F-box) and APC/C (Anaphase Promoting Complex/Cyclosome) family of ubiquitin ligases. In a mass spectrometry based screen for novel substrates of the SCF, a potential link to the regulation of the DNA replication and DNA damage checkpoints of the mammalian cell cycle was found. This connection stems from the identification of the DNA replication checkpoint molecule Claspin as a potential SCF substrate. It is the aim of the proposed research fellowship to characterize the mechanism by which SCF based ubiquitination contributes to the regulation of mammalian DNA replication and DNA damage checkpoints and how deregulation of this mechanism may be involved in tumorigenesis.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Gastgeber: Professor Dr. Michele Pagano