Protein modifications by the covalent linkage of ubiquitin have significant involvement in many cellular processes, including stress response, oncogenesis, viral infection, transcription, protein turnover, organelle biogenesis, DNA repair, cellular differentiation, and cell cycle control. We provide a brief overview of the fundamentals of the regulation of protein turnover by the ubiquitin-proteasome pathway and discuss new therapeutic strategies that aim to mitigate the deleterious effects of its dysregulation in cancer and other human disease pathophysiology. 1. Introduction The timely degradation of many transiently induced and/or oscillatory proteins is fundamental to the maintenance of diverse biological processes, including receptor trafficking, cell cycle progression, DNA repair, gene transcription, autophagy, and programmed cell death [1–7]. Dysregulation of such regulatory mechanisms has been reported to underlie a growing list of human diseases including cancers, neurodegenerative diseases, and inflammatory and autoimmune disorders. Clearance of intracellular proteins in the cell occurs primarily in three highly specialized subcellular organelles—the proteasome, the lysosome, and the autophagosome. A small protein modifier, ubiquitin, appears to be the common denominator in the targeting of substrates to these degradation pathways in mammalian cells. In this review, we discuss the molecular basis of the ubiquitin-proteasome degradation pathway, the human diseases commonly associated with its dysregulation, and the potential for pharmacologic targeting of the ubiquitin-proteasome pathway as a novel therapeutic approach. 2. Biological Functions of the Ubiquitin-Proteasome System (UPS) 2.1. The Core UPS Machinery As depicted in Figure 1, ubiquitination of target proteins is achieved through the functional orchestration of three classes of enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugation enzyme), and E3 (ubiquitin ligase). Ubiquitin, in an initial energy-dependent step, associates with these enzymatic components through a labile thioester linkage. This facilitates its covalent ligation to the target through a more stable isopeptide linkage to the ε-amino group of acceptor lysine residues or, less frequently, the amino terminus. The enzymatic cascade of ubiquitination is characterized by extensive combinatorial complexity and specificity, as dictated by the diversity of its constituent enzymes: two known E1s, tens of E2s, and hundreds of E3s [2]. Figure 1: Targeting the UPS of protein turnover in cancer and other human diseases.
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