Key Points
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Two major classes of ubiquitin ligases, the SKP1–CUL1–F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), have a central role in cell-cycle regulation.
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The SCF complex and APC/C are structurally similar. Each is constituted of common subunits and a variable substrate-recognition subunit (F-box proteins for the SCF complex and activators for the APC/C). Three F-box proteins in the SCF complex — S-phase kinase-associated protein 2 (SKP2), F-box and WD-40 domain protein 7 (FBW7) and β-transducin repeat-containing protein (β-TRCP) — and two activators in the APC/C — cell division cycle 20 (CDC20) and CDH1 (also known as HCT1) — are the most important in cell-cycle regulation.
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SKP2 targets negative regulators of the cell cycle such as p27, p21 and p57 for degradation, and thereby promotes cell-cycle progression during S and G2 phases. SKP2 is upregulated in many human cancers.
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FBW7 induces the degradation of positive regulators of the cell cycle, such as MYC, JUN, cyclin E and Notch. FBW7 is often mutated in a subset of human cancers.
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β-TRCP is a versatile F-box protein that recognizes several cell-cycle regulators — EMI1/2, WEE1A and CDC25A/B — in addition to its classical substrates, β-catenin and IκB. In some cancers, β-TRCP mutation or overexpression is found.
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CDC20 targets securin and mitotic cyclins for destruction, and thereby promotes sister-chromatid separation. CDC20 is the crucial mediator of the spindle checkpoint, which prevents aneuploidy and genomic instability. CDC20 is overexpressed in some cancers, although in others the CDC20 gene is mutated or deleted.
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CDH1 facilitates exit from M phase and maintains G1 phase by mediating the degradation of mitotic cyclins, non-CDK (cyclin-dependent kinase) mitotic kinases and some regulators of the formation of pre-replicative complexes. Deregulated expression or mutation of CDH1 as well as of most CDH1 targets have been described in human cancers.
Abstract
A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1–CUL1–F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.
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Acknowledgements
The authors wish to thank all members of our laboratories for their comments. We are also thankful to A. Ohta and M. Kimura for help in preparing this manuscript. This research was partly supported by a grant from CREST, Japan Science and Technology Agency.
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Supplementary table S1, supplementary references and figures S2-S3 (PDF 405 kb)
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Glossary
- Cyclin-dependent kinase
-
A protein kinase that controls cell-cycle progression in all eukaryotes and requires physical association with cyclins to achieve full enzymatic activity.
- Cyclin
-
The positive regulatory subunits of cyclin-dependent kinases, showing oscillating expression in the cell cycle.
- Ubiquitin
-
A 76-amino-acid polypeptide that is conjugated through an isopeptide linkage to other proteins. Such conjugates are most commonly targeted for degradation by the proteasome.
- Proteasome
-
A large ∼2.5-MDa multisubunit protein complex that binds to and subsequently degrades polyubiquitylated proteins in an ATP-dependent manner.
- Ubiquitin-conjugating enzyme (E2)
-
An enzyme that accepts ubiquitin from a ubiquitin-activating enzyme (E1) and, together with a ubiquitin ligase (E3), transfers it to a substrate protein.
- Ubiquitin ligase (E3)
-
A protein or protein complex that facilitates the transfer of ubiquitin from a ubiquitin-conjugating enzyme (E2) to a substrate. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating the ubiquitylation of the selected substrate.
- Cullins
-
A family of proteins that are characterized by the presence of a distinct globular C-terminal domain (cullin homology domain) and a series of N-terminal repeats of a five helix bundle (cullin repeats).
- F-box protein
-
A variable component of SCF E3 ligase that binds to SKP1 through the Fbox domain. FBPs recognize specific substrates and, with the help of other subunits of the E3 ubiquitin ligase, deliver them to the E2 ubiquitin-conjugating enzyme.
- RING-finger proteins
-
A family of proteins structurally defined by a particular folded protein domain that binds Zn2+ through a four-point arrangement of cysteine and histidine amino acids. In most cases, a RING-finger protein interacts with an E2 and serves as an E3.
- WD40 repeat
-
A protein-interaction domain consisting of 40 amino-acid repeats that form a propeller-like structure, in which each repeat contributes a blade.
- Leucine-rich repeat
-
A protein-sequence motif that contains regular occurrences of the amino acid leucine, which are present as tandem arrays in certain proteins. The back-to-back set of motifs was found to correspond to a small sub-domain structure in the protein that stacks next to adjacent repeats to form a parallel, β-sheet, arc-like structure.
- Degron
-
A portion of a protein that is necessary and sufficient to bring about its degradation by the ubiquitin–proteasome system.
- Spindle
-
A highly dynamic, bipolar array of microtubules that forms during mitosis or meiosis and serves to move the duplicated chromosomes apart.
- Kinetochore
-
The complicated protein assembly that links the specialized areas of condensed chromosomes, known as centromeres, to the microtubule-based mitotic spindle.
- Aneuploidy
-
The ploidy of a cell refers to the number of sets of chromosomes that it contains. Aneuploid karyotypes are those of which chromosome complements are not a simple multiple of the haploid set.
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Nakayama, K., Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6, 369–381 (2006). https://doi.org/10.1038/nrc1881
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DOI: https://doi.org/10.1038/nrc1881
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