title: Ubiquitin-dependent proteolysis: its role in human diseases and the design of therapeutic strategies.
abstract: Protein degradation is one of the tactics employed by the cell for irreversibly inactivating proteins. In eukaryotes, ATP-dependent protein degradation in the cytoplasm and nucleus is carried out by the 26S proteasome. Most proteins are targeted to the 26S proteasome by covalent attachment of a multi-ubiquitin chain. A key component of the enzyme cascade that results in attachment of the multi-ubiquitin chain to the target or labile protein is the ubiquitin ligase that controls the specificity of the ubiquitination reaction. Defects in ubiquitin-dependent proteolysis have been shown to result in a variety of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders. This review focuses on the role of ubiquitin-dependent degradation in human disease and potential clinical applications that are being developed to exploit the cells natural proteolytic machinery to treat diseases.
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D017204:Angelman Syndrome / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008025:Ligases / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D044843:SKP Cullin F-Box Protein Ligases; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D002583:Uterine Cervical Neoplasms / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism
chemical_list: C471644:BTRC protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D019204:GTP-Binding Proteins; D008025:Ligases; C067419:CBL protein, human; D010453:Peptide Synthases