Roles of the Ubiquitin System in Health and Disease Abstract The selective degradation of many short–lived proteins in eukaryotic cells is carried out by the ubiquitin-mediated proteolytic system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. The ligation of ubiquitin to protein involves the successive action of three types of enzymes: the ubiquitin-activating enzyme E1, a ubiquitin-carrier protein E2 and a ubiquitin-protein ligase, E3. The selectivity and the regulation of the degradation of a specific protein are usually determined by the properties of its specific ubiquitin ligase (E3) enzyme. We have been studying two ubiquitin ligase complexes that have important roles in different aspects of cell cycle regulation. One is the cyclosome, or Anaphase-Promoting Complex (APC/C), which acts on mitotic cyclins and some other cell cycle regulators in exit from mitosis. The APC/C is activated at the end of mitosis by phosphorylation, a process that allows its further activation by the ancillary protein Cdc20. A different complex, which belongs to the SCF (Skp1-Cullin-F-box protein) family of ubiquitin ligases, is involved in the degradation of p27, a mammalian G1 Cdk inhibitor, following mitogenic stimulation. Its action is triggered by Cdk2-dependent phosphorylation of p27, as well as by the increase in levels of a specific F-box protein, Skp2, that takes place in the G1 to S-phase transition. Work from other laboratories has shown that ubiquitin-mediated degradation of regulatory proteins is involved in a large variety of basic biological processes including the control of cell proliferation, inflammation and immunity, embryonic development, signal transduction and gene expression. Abnormalities in protein degradation are involved in diseases such as some types of cancer and neurodegenerative disorders. The mode of the involvement of the ubiquitin system in cancer will be discussed in some detail. References: Hershko, A. (2005) The ubiquitin system for protein degradation and some of its roles in the control of cell division (Nobel lecture). Cell Death Differ. 12, 1191-1197. Hershko, A. (2009) Some lessons from my work on the biochemistry of the ubiquitin system. J. Biol. Chem. 284, 10291-10295. Hershko, A. (2010) From rabbit reticulocytes to clam oocytes: in search of the system that targets mitotic cyclins for degradation. Mol. Biol. Cell 21, 1645-1647.