The
ubiquitin-
proteasome system plays a critical role in controlling the level, activity and location of various cellular
proteins. Significant progress has been made in investigating the molecular mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying
ubiquitin protein ligases, the primary specificity-determining
enzymes. Therefore, it is now possible to target specific molecules involved in ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all,
cancer cells. This is manifested by destabilization of
tumor suppressors, such as p53, and overexpression of oncogenes such as c-Myc and c-Jun. In addition to the development and clinical validation of
proteasome inhibitor,
bortezomib, in myeloma
therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination
enzymes. With the help of structural studies, rational design and chemical synthesis, it is conceivable that we will be able to use 'druggable' inhibitors of the
ubiquitin system to evaluate their effects in animal
tumor models in the not-so-distant future.