Mechanisms of delivery of ubiquitylated proteins to the proteasome:: new target for anti-cancer therapy?

The proteasome is the main proteolytic machinery of the cell. It is responsible for the basal turnover of many intracellular polypeptides, the elimination of abnormal proteins and the generation of the vast majority of peptides presented by class I major histocompatibility complex molecules. Proteasomal proteolysis is also involved in the control of virtually all cellular functions and major decisions through the spatially and timely regulated destruction of essential cell regulators. Therefore, the elucidation of its molecular mechanisms is crucial for the full understanding of the physiology of cells and whole organisms. Conversely, it is increasingly clear that proteasomal degradation is either altered in numerous pathological situations, including many cancers and diseases resulting from aberrant cell differentiation, or instrumental for the development of these pathologies. This, consequently, makes it an attractive target for therapeutical intervention. There is ample evidence that most cell proteins must be polyubiquitylated prior to proteasomal degradation. If the structure and the mode of functioning of the proteasome, as well as the enzymology of ubiquitylation, are relatively well understood, how substrates are delivered to and recognized by the proteolytic machine has remained mysterious till recently. The recent literature indicates that the mechanisms involved are multiple, complex and exquisitely regulated and provides new potential targets for anti-cancer pharmacological intervention. (C) 2004 Elsevier Ireland Ltd. All rights reserved.