The ubiquitin proteasome system is important for nearly every aspect of cellular life. It provides the cell the ability to specifically and temporally degrade proteins. To do this, it tags substrates with ubiquitin chains. This tagging targets them to the proteasome where they are degraded. In order to degrade ubiqutinated proteins, the proteasome possesses ubiquitin binding, deubiquitinating and unfolding activities, all of which are required for degradation. CHAPTER I REVIEW OF THE LITERATURE

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... DISCOVERY AND OVERVIEW OF THE UBIQUITIN PROTEASOME SYSTEM Though it is very clear today that protein degradation is vital for cellular life, this was not always thought to be the case. Previous to the discovery of the lysosome by Christian de Duve (1;2), it was widely thought that the proteins of the cell were stable and not readily turned over. Regulation of cellular activity was thought to be controlled mainly through production of proteins by transcriptional and translational control. With the discovery of the lysosome and pioneering studies using radioactively labeled amino acids, it eventually became clear that cellular proteins were being constantly made and degraded (3-5). This may have been attributed to the lysosome. However, further studies of protein degradation gave researchers clues that the lysosomal pathway may not be the only means by which the cell could degrade proteins. Aaron Ciechanover recalled in an article, 'accumulating lines of independent evidence indicated degradation of at least certain classes of cellular proteins must be nonlysosomal' (6). For instance, lysosomal inhibitors could strongly inhibit the degradation of some proteins but not others (7). Also, studies found that proteins could have very different half lives that varied from hours to days (8). This would not likely be the case if lysosomal degradation were the only means of degradation because in this model bulk proteins were randomly gathered into membranous vesicles and recycled by lysosomes. Finally, studies of hemoglobin using reticulocytes, which contain no lysosomes, showed that damaged or abnormal hemoglobin was quickly degraded in these cells (9). Altogether, there was mounting evidence for a non-lysosomal mechanism for protein destruction. Vital studies by Etlinger and Goldberg developed a cell-free system using reticulocyte lysates and showed that degradation of the altered hemoglobin was stimulated by ATP (10;11).