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Ubiquitin ligases and cancer

The ubiquitin-proteasome system controls molecular networks that underlie fundamental cellular functions such as DNA replication, DNA repair, transcription, protein synthesis, cell differentiation and apoptosis. Aberrant functions for components of the ubiquitin-proteasome system (particularly for ubiquitin ligases that provide substrate specificity) have been implicated in the pathogenesis of many human cancers. Mutational inactivation of the machinery involved in linking ubiquitin to specific substrates can occur in ubiquitin ligases involved in restraining cell growth and proliferation (e.g. the tumor suppressor F-box protein Fbw7) or in ubiquitin ligases implicated in DNA repair and genome integrity (for example, breast cancer type 1 susceptibility protein (Brca1)). Furthermore, overexpression of genes encoding for ubiquitin ligases is linked to tumorigenesis, like in the case of Mdm2 and the F-box protein Skp2, which mediate the degradation of the tumor suppressors p53 and p27, respectively. In addition, targets of the ubiquitin-proteasome system (e.g. c-Myc and beta-catenin) are frequently mutated in human tumors. The target protein, normally programmed for degradation, becomes mutated in residues that are required for recognition by the ubiquitin ligase, making this protein resistant to the action of the degradation machinery.

E3 ubiquitin ligases are responsible for the specific recognition of a large number of target proteins. This requires specificity and versatility, which are provided by the existence of about 1000 different ligases. The RING-finger-type E3s are thought to be the largest family and are further divided into subfamilies; one of these, the cullin-based E3 subfamily, is one of the largest single classes of E3s. There are seven cullin-based E3s, and many of these are involved in the ubiquitinylation of cancer-related substrates. The Skp1-Cul1-F-box-protein (SCF) ubiquitin ligases consist of three invariable components: Rbx1 (Ring-finger protein), Cul1 (scaffold protein) and Skp1 (adaptor protein), as well as one variable component, known as an F-box-protein, which binds through its F-box motif to Skp1 and is responsible for substrate recognition.

The main objective of our research is to investigate how altered functions of the ubiquitin-proteasome system contribute to oncogenesis. To this end, we use an interdisciplinary approach that includes biochemical and cellular biological methods as well as mouse genetics.

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