Evelyn McGown, Ph.D., Jinfang Liao, M.D., Ph.D., Molecular Devices Corporation, 1311 Orleans Dr., Sunnyvale, CA 94089 and Olivier Dery, BD Biosciences Clontech, Palo Alto, CA.
Proteins inside eukaryotic cells exist in a dynamic state, in a highly-regulated balance between synthesis and degradation. Whereas protein synthesis is well-understood after decades of study, major advances in our knowledge of protein degradation have occurred only in the last two decades. As a result, the 2004 Nobel prize in chemistry was awarded to Aron Ciechanover, Avram Hershko and Irwin Rose for their discovery of ubiquitin-mediated proteolysis, an ATP-dependent process where unwanted proteins are multiply-tagged with ubiquitin (a 76-amino acid protein).1 The tagged proteins are then transported to the proteasome for degradation. The proteasome is a massive (2.5 MDa), barrel-shaped protein complex inside all eukaryotic cells (and some bacteria) that consists of a tunnel-like core with a cap at each end. (See Figure 1.) The caps (regulatory complexes) recognize and bind targeted proteins and inject them into the central core where the proteins are successively degraded into short peptides.
Numerous cellular processes regulated by ubiquitin-mediated proteolysis include cell cycle, differentiation, DNA repair and transcription, stress response, neuronal morphogenesis, cell surface receptor modulation, secretion, regulation, long-term memory, circadian rhythms and immune response.2 Defects in ubiquitinmediated proteolysis are implicated in the pathogenesis of many human diseases, including a variety of cancers. Thus it is not surprising that this has become the target for development of drugs against various diseases. One drug, already in clinical trials, is the proteasome inhibitor Velcade which is approved for treatment of multiple myeloma.(
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