Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer

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Abstract
Targeted protein proteolysis of key regulatory proteins by the ubiquitin–proteasome system (UPS) has a central role in maintaining and regulating growth. As such, components of the UPS can promote or prevent cellular transformation, which results from an aberrant response to otherwise normal cues that regulate processes involved in proliferation, differentiation and apoptosis. The SCF (SKP1–CUL1–F-box protein) ubiquitin ligases are the best characterized mammalian cullin RING ubiquitin ligases, and the F-box protein provides the substrate targeting specificity of the complex. Out of sixty-nine F-box proteins that have been identified in humans, only nine have been matched with their respective substrates. The F-box proteins SKP2 (S-phase kinase-associated protein 2) and β-TrCP (β-transducin repeat-containing protein) have emerged as key regulatory molecules with roles in cellular processes that are intimately related to tumorigenesis. SKP2 is an oncogenic protein that targets tumour suppressor proteins for degradation. As a positive regulator of cell cycle progression, a major target of SKP2 is the cyclin-dependent kinase (CDK) inhibitor p27, as has been shown in vivo and in vitro. Increased levels of SKP2 and reduced levels of p27 are observed in many types of cancer, and these levels are in several cases used as independent prognostic markers. Whereas β-TrCP has been previously suggested to possess both oncogenic and tumour suppressive characteristics — mainly owing to the diversity in β-TrCP substrates — recent evidence indicates β-TrCP is mainly oncogenic. Previous attempts at targeting components of the degradation machinery have been successful for laboratory and clinical use, as observed in the effectiveness of the proteasome inhibitor bortezomib (Velcade) in multiple myeloma. The development of pharmaceutical compounds targeting specific SCF ubiquitin ligases is timely and is complemented by structural and basic biochemical studies that have identified substrates for important cellular regulators such as SKP2 and β-TrCP.