Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Systematic analysis and nomenclature of mammalian F-box proteins. The COP9 signalosome: more than a protease. Building and remodelling Cullin-RING E3 ubiquitin ligases. HECT and RING finger families of E3 ubiquitin ligases at a glance. New insights into ubiquitin E3 ligase mechanism. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Ubiquitin-based anticancer therapy: carpet bombing with proteasome inhibitors versus surgical strikes with E1, E2, E3, or DUB inhibitors. Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma. Kubiczkova, L., Pour, L., Sedlarikova, L., Hajek, R. Novel proteasome inhibitors to overcome bortezomib resistance. Molecular mechanisms of bortezomib resistant adenocarcinoma cells. Regulation of proteasome activity in health and disease. Mechanisms and function of substrate recruitment by F-box proteins. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. A genomic and functional inventory of deubiquitinating enzymes. Linear ubiquitination: a newly discovered regulator of cell signalling. This Review explores and discusses potential strategies to target SCF-mediated biological processes to treat human diseases. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. SCF ubiquitin ligases are characterized by their high specificity for substrates, and these ligases therefore represent promising drug targets.
Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a multitude of processes at the cellular and organismal levels, and their dysregulation is implicated in many pathologies. F-box proteins are the substrate-targeting subunits of SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complexes. Increased specificity could be achieved by inhibiting the components of the ubiquitin–proteasome system that target specific subsets of proteins for degradation. However, proteasome inhibitors prevent the degradation of numerous proteins, which may cause adverse effects. The clinical successes of proteasome inhibitors for the treatment of cancer have highlighted the therapeutic potential of targeting this protein degradation system. Several compounds targeting E3 ligases have been developed, hinting that effective drugs targeting other SCF ubiquitin ligase activities may also be developed. In cases in which SCF activity is defective in disease, SCF activity can by reconstituted through bivalent small molecules that re-target the substrate and/or 'molecular glue'-like molecules that restore substrate–F-box protein binding.Īlthough an underdeveloped area, SCF complexes are promising drug targets, and as the substrates and functions of orphan F-box proteins are discovered, further drug targets will become apparent. In cases in which an SCF complex is overactive, the inhibition of SCF-mediated degradation can be achieved via competitive inhibition between substrate and F-box protein, allosteric inhibition that disrupts the interaction between substrate and F-box protein, or via the inhibition of SCF complex assembly. SCF complexes are dysregulated in several diseases by overexpression of the F-box protein, by mutation (genetic deletion or point mutations) of the F-box protein, or by disrupting the pathways that control F-box protein–substrate targeting. In mammals, there are approximately 70 F-box proteins, each thought to be able to target multiple substrates, facilitating the regulation of diverse cellular pathways. In certain cases, the specific inhibition of individual components of the UPS may provide better therapeutic outcomes than does broad inhibition of the proteasome.į-box proteins are the targeting subunits of the SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes, the best characterized of the mammalian cullin–RING ligase family of E3 ubiquitin ligases. The ubiquitin–proteasome system (UPS) has links to numerous diseases, and the clinical success of proteasome inhibitors suggests the potential to develop drugs targeting other components of the UPS.