Alternative UPS drug targets upstream the 26S proteasome

The successful use of proteasome inhibitors in anti-cancer therapy encouraged the development of new drugs targeting the activity of the ubiquitin-proteasome system (UPS) at various levels. The UPS comprises a complex set of protein adaptors whose coordinated function modulates the interaction of ubiquitin-modified proteins with protein effectors. In addition, UPS crosstalk with other post-translational modifications, complicates a sophisticated set of conjugation and de-conjugation pathways, providing a large variety of potential targets for the development of specific inhibitors. Traditionally associated with the proteasome, ubiquitin-conjugation does not always result in protein degradation. The major signal that targets proteins for degradation is the formation of ubiquitin-chains on lysine 48 (K48). Other ubiquitin features such as K63 chains or mono-ubiquitylation appear to regulate the transient formation of functional macromolecular complexes or relocate modified proteins inside the cell. The emerging idea that UPS-mediated degradation participates not only in the initiation but also in the termination step of certain functions, highlights new potential drug targets upstream the 26S proteasome. This review underlines some of these, in particular, possibilities for intervention before the recognition of substrates by the ubiquitin-conjugating enzymes and after the conjugation of target proteins with ubiquitin. To illustrate possible therapeutic targets at the level of transcription, subcellular distribution and signal transduction pathways, NF-kappaB and p53 have been used as main examples in this review.