Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
The maintenance and preservation of distinct phases during the cell cycle is a highly complex and coordinated process. It is regulated by phosphorylation — through the activity of cyclin-dependent kinases (CDKs) — and protein degradation, which occurs through ubiquitin ligases such as SCF (SKP1–CUL1–F-box protein) complexes and APC/C (anaphase-promoting complex/cyclosome). Here, we explore the functionality and biology of the F-box proteins, SKP2 (S-phase kinase-associated protein 2) and β-TrCP (β-transducin repeat-containing protein), which are emerging as important players in cancer biogenesis owing to the deregulated proteolysis of their substrates.
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Acknowledgements
We thank S. Fuchs, Y. Ben-Neriah, K. Nakayama and J. Skaar for critically reading the manuscript. We apologize to colleagues whose work could not be mentioned owing to space limitations. D.F. is grateful to A. Nans. M.P. is grateful to T. M. Thor for continuous support. Work in the Pagano laboratory is supported by grants from the NIH (R37-CA76,584, R01-GM57,587, R21-CA125,173 and P30-CA01687) and the Multiple Myeloma Research Foundation senior award.
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Glossary
- Ubiquitin
-
A small, 7.5-kDa protein that is ubiquitously expressed in all eukaryotes. Chains of ubiquitin moieties (connected by Lys48) target proteins for proteasomal degradation. Monoubiquitylation or polyubiquitylation through different lysine residues controls the function (not the proteolysis) of various proteins.
- Proteasome
-
A large multisubunit protein complex (approximately 2.5 MDa) that is found in all eukaryotes and archaea, the main function of which is to degrade excessive, unneeded or damaged proteins by proteolysis using a chemical reaction that breaks peptide bonds in an ATP-dependent manner.
- Ubiquitin-activating enzyme (E1)
-
An enzyme that activates ubiquitin in a process that requires ATP as an energy source.
- Ubiquitin-conjugating enzyme (E2)
-
An enzyme that accepts the transfer of ubiquitin from the ubiquitin-activating enzyme (E1) and transfers it to substrates.
- Ubiquitin ligase (E3)
-
An enzyme that functions as the substrate recognition component of the ubiquitylation machinery. E3 enzymes are capable of interacting with E2 enzymes and substrates to facilitate the transfer of ubiquitin to the selected substrate.
- RING-finger proteins
-
Proteins that interact with E2 ubiquitin enzymes to serve as an E3 enzyme. They are subdivided structurally into multi-subunit and single-subunit types, including those containing RING-like folds such as the U-box.
- HECT-domain proteins
-
Proteins that are characterized by the presence of a C-terminal HECT domain, which is a domain of approximately 350 amino acids that is catalytically involved in the attachment of ubiquitin to substrates.
- F-box domain
-
Originally identified in cyclin F as a stretch of approximately 40 amino acids linking F-box proteins to SKP1 to form the core of the SCF complex.
- Degron
-
Specific sequence of amino acids in a protein substrate typically conserved through evolution that directs the recognition of an E3 ubiquitin ligase.
- Paralogues
-
Homologous genes that have resulted from a gene duplication event within a single genome. This is in contrast to othologous genes, which are separated by a speciation event.
- C phase
-
The mammalian cell cycle is divided into four distinct phases called G1, S, G2 and mitosis. C phase is defined as the temporal interval between the G1–S transition and the end of mitosis when CDK activity is present.
- Organomegaly
-
The abnormal enlargement of organs.
- Mitotic catastrophe
-
A death resulting from failure of a cell to arrest before mitosis following DNA damage, resulting in severe aberrancies in chromosomal structure and segregation. It might share downstream events with apoptosis.
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Frescas, D., Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nat Rev Cancer 8, 438–449 (2008). https://doi.org/10.1038/nrc2396
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DOI: https://doi.org/10.1038/nrc2396
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