Ubiquitin-dependent proteolysis: its role in human diseases and the design of therapeutic strategies

Mol Genet Metab. Sep-Oct 2002;77(1-2):44-56. doi: 10.1016/s1096-7192(02)00146-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / metabolism
  • Angelman Syndrome / metabolism
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Female
  • GTP-Binding Proteins / metabolism
  • Hepatolenticular Degeneration / genetics
  • Hepatolenticular Degeneration / metabolism
  • Humans
  • Ligases / metabolism
  • Male
  • Models, Biological
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Peptide Synthases / metabolism
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-cbl
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases
  • Uterine Cervical Neoplasms / metabolism
  • beta-Transducin Repeat-Containing Proteins
  • von Hippel-Lindau Disease / genetics
  • von Hippel-Lindau Disease / metabolism

Substances

  • BTRC protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • Ubiquitin
  • beta-Transducin Repeat-Containing Proteins
  • Proto-Oncogene Proteins c-cbl
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases
  • GTP-Binding Proteins
  • Ligases
  • CBL protein, human
  • Peptide Synthases