Frank van Drogen
Cell cycle regulation by SCFCdc4-dependent degradation of APC subunits in mammalian cells
Cell division requires the precise orchestration of a number of irreversible events. This regulation is provided by transcription, phosphorylation and degradation of key cell cycle regulators by ubiquitin-dependent proteolysis. Deregulation of substrate turnover is an underlying mechanism of many human disorders, and multiple E3 ligase components have been shown to function as tumor suppressors or proto-oncogenes. Cullin-based SCF (Skp, Cullin, F-box) and the APC/C (anaphase promoting complex C/cyclosome) are among the best studied RING-H2 E3 ubiquitin ligases, and are critical regulators of cell cycle progression. However, their physiological substrates and regulatory mechanisms are still poorly understood.
The F-box protein hCdc4 functions as a substrate-specific adaptor in a cullin1-based SCF E3-ligase complex, and is required for the rapid turnover of a number of proto-oncogenes including c-Myc, c-Jun and cyclin E. The aim of my project is to identify and functionally characterize degradation of novel hCdc4-substrates, in particular the turn-over of specific APC subunits by SCFhCdc4.