CDC20
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Location (UCSC) | Chr 1: 43.36 – 43.36 Mb | Chr 4: 118.29 – 118.29 Mb | |||||||
PubMed search | [3] | [4] |
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The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20
CDC20 appears to act as a regulatory protein interacting with many other proteins at multiple points in the cell cycle. It is required for two microtubule-dependent processes: nuclear movement prior to anaphase, and chromosome separation.[7]
Discovery
CDC20, along with a handful of other Cdc proteins, was discovered in the early 1970s when Hartwell and colleagues made cell-division cycle mutants that failed to complete major events in the cell cycle in the yeast strain S. cerevisiae.[8] Hartwell found mutants that did not enter anaphase and thus could not complete mitosis; this phenotype could be traced back to the CDC20 gene.[9] However, even after the biochemistry of the protein was eventually elucidated, the molecular role of CDC20 remained elusive until the discovery of the APC/C in 1995.[10][11]
Structure
CDC20 is a protein related to the beta subunit of heterotrimeric G proteins. Near its C-terminus it contains seven WD40 repeats, which are multiple short, structural motifs of around 40 amino acids that often play a role in binding with larger protein complexes. In the case of CDC20, they arrange into a seven-bladed beta propeller. The human CDC20 is about 499 amino acids long, and contains at least four phosphorylation sites near the N-terminus. In between these phosphorylation sites, which play regulatory roles, are the C-box, the KEN-box, the Mad2-interacting motif, and the Cry box. The KEN-box, as well as the Cry box, are important recognition and degradation sequences for the APC/CCdh1 complex (see below).
Interactions
CDC20 has been shown to
- ANAPC7[12][13]
- BUB1B,[13][14][15][16][17][18]
- CDC16,[12][13][16][19]
- CDC27,[12][13][16][19][20][21][22]
- Cyclin A1,[23]
- FBXO5,[24]
- HDAC1,[25]
- HDAC2,[25] and
- MAD2L1.[13][16][18][19][20][21][26][27][28][29][30][31]
However, the most important interaction of CDC20 is with the Anaphase Promoting Complex. The APC/C is a large E3 ubiquitin ligase, which triggers the metaphase to anaphase transition by marking select proteins for degradation. The two main targets of the APC/C are the S/M cyclins and the protein securin. S/M cyclins activate cyclin-dependent kinases (Cdks), which have a vast array of downstream effects that work to guide the cell through mitosis. They must be degraded for cells to exit mitosis. Securin is a protein that inhibits separase, which in turn inhibits cohesin, a protein that holds sister chromatids together. Therefore, in order for anaphase to progress, securin must be inhibited so that cohesin can be cleaved by separase. These processes are dependent on both the APC/C and CDC20: When Cdks phosphorylate the APC/C, CDC20 can bind and activate it, allowing both the degradation of Cdks and the cleavage of cohesin. APC/C activity is dependent on CDC20 (and Cdh1), because CDC20 often binds the APC/C substrates directly.[32] In fact, it is thought that CDC20 and Cdh1 (see below) are receptors for the KEN-box and D-box motifs on substrates.[33] However, these sequences are normally not sufficient for ubiquitination and degradation; much remains to be learned about how CDC20 binds its substrate.
Regulation
The APC/CCdc20 complex regulates itself so that it is present during the appropriate times of the cell cycle. In order for CDC20 to bind the APC/C, specific APC/C subunits must be phosphorylated by Cdk1 (among other Cdks). Therefore, when cdk activity is high in mitosis, and the cell must prepare to enter anaphase and exit mitosis, the APC/CCdc20 complex is activated. Once active, APC/CCdc20 promotes the degradation of Cdks by inactivating S/M cyclins. Cdk degradation brings about lower rates of APC/C phosphorylation and thus lower rates of CDC20 binding. In this way, the APC/CCdc20 complex inactivates itself by the end of mitosis.[34] However, because the cell does not immediately enter the cell cycle, Cdks can not immediately be reactivated. Multiple different mechanisms inhibit Cdks in G1: Cdk inhibitor proteins are expressed, and cyclin gene expression is down-regulated. Importantly, cyclin accumulation is also prevented by Cdh1.[34]
Cdh1
CDC20-homologue 1 (Cdh1) plays a complementary role to CDC20 in cell cycle progression. During the time of APC/CCdc20 activity, Cdh1 is phosphorylated and cannot bind to the APC/C. After metaphase, however, S/M-Cdks are inactivated by APC/CCdc20, and Cdh1 can exist in a non-phosphorylated state and bind the APC/C. This enables the APC/C to continue to degrade S/M cyclins (and thus S/M Cdks) until they are needed again in the next S-phase. How can S/M cyclins reappear to shepherd the cell into mitosis? The APC/CCdc20 does not recognize G1/S cyclins. Their concentration rises during G1, activating G1/S Cdks, which in turn phosphorylate Cdh1 and gradually relieve the inhibition on S/M cyclins.[34]
Spindle assembly checkpoint
CDC20 is also a part of, and regulated by, the
Cancer
CDC20 is often elevated in cancerous tissues for multiple kinds of cancer. It is correlated with aggressiveness in breast cancer: higher levels are associated with poorer outcomes. CDC20 overexpression has also been reported in lung, gastric, and pancreatic cancers. For gastric and pancreatic cancers, higher levels are correlated with
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000117399 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006398 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 7513050.
- PMID 9353311.
- ^ "Entrez Gene: CDC20 cell division cycle 20 homolog (S. cerevisiae)".
- PMID 5271168.
- PMID 17248617.
- S2CID 16958690.
- PMID 7787245.
- ^ S2CID 5942532.
- ^ PMID 18997788.
- PMID 11907259.
- S2CID 23544995.
- ^ PMID 12196507.
- PMID 11535616.
- ^ PMID 11274370.
- ^ PMID 9628895.
- ^ PMID 14561775.
- ^ PMID 9736712.
- S2CID 17181162.
- PMID 10679238.
- S2CID 25403043.
- ^ S2CID 21762011.
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- PMID 14607335.
- S2CID 1721494.
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- ^ ISBN 978-0-87893-508-6.
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- .
Further reading
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. PMID 9373149.
- Kallio M, Weinstein J, Daum JR, Burke DJ, Gorbsky GJ (1998). "Mammalian p55CDC Mediates Association of the Spindle Checkpoint Protein Mad2 with the Cyclosome/Anaphase-promoting Complex, and is Involved in Regulating Anaphase Onset and Late Mitotic Events". J. Cell Biol. 141 (6): 1393–406. PMID 9628895.
- Fang G, Yu H, Kirschner MW (1998). "The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation". Genes Dev. 12 (12): 1871–83. PMID 9637688.
- Weinstein J, Karim J, Geschwind DH, Nelson SF, Krumm J, Sakamoto KM (1998). "Genomic organization, 5' flanking enhancer region, and chromosomal assignment of the cell cycle gene, p55Cdc". Mol. Genet. Metab. 64 (1): 52–7. PMID 9682218.
- Fang G, Yu H, Kirschner MW (1998). "Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1". Mol. Cell. 2 (2): 163–71. PMID 9734353.
- Wassmann K, Benezra R (1998). "Mad2 transiently associates with an APC/p55Cdc complex during mitosis". Proc. Natl. Acad. Sci. U.S.A. 95 (19): 11193–8. PMID 9736712.
- Kramer ER, Gieffers C, Hölzl G, Hengstschläger M, Peters JM (1999). "Activation of the human anaphase-promoting complex by proteins of the CDC20/Fizzy family". Curr. Biol. 8 (22): 1207–10. S2CID 17181162.
- Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C (1999). "Characterization of MAD2B and other mitotic spindle checkpoint genes". Genomics. 58 (2): 181–7. PMID 10366450.
- Farruggio DC, Townsley FM, Ruderman JV (1999). "Cdc20 associates with the kinase aurora2/Aik". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7306–11. PMID 10377410.
- Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Hatakeyama M (2000). "Human p55(CDC)/Cdc20 associates with cyclin A and is phosphorylated by the cyclin A-Cdk2 complex". Biochem. Biophys. Res. Commun. 268 (2): 530–4. PMID 10679238.
- Luo X, Fang G, Coldiron M, Lin Y, Yu H, Kirschner MW, Wagner G (2000). "Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20". Nat. Struct. Biol. 7 (3): 224–9. S2CID 1721494.
- Wu H, Lan Z, Li W, Wu S, Weinstein J, Sakamoto KM, Dai W (2000). "p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase". Oncogene. 19 (40): 4557–62. S2CID 23544995.
- Skoufias DA, Andreassen PR, Lacroix FB, Wilson L, Margolis RL (2001). "Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4492–7. PMID 11274370.
- Reimann JD, Freed E, Hsu JY, Kramer ER, Peters JM, Jackson PK (2001). "Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex". Cell. 105 (5): 645–55. S2CID 16366514.
- Zhang Y, Lees E (2001). "Identification of an Overlapping Binding Domain on Cdc20 for Mad2 and Anaphase-Promoting Complex: Model for Spindle Checkpoint Regulation". Mol. Cell. Biol. 21 (15): 5190–9. PMID 11438673.
- Chen J, Fang G (2001). "MAD2B is an inhibitor of the anaphase-promoting complex". Genes Dev. 15 (14): 1765–70. PMID 11459826.
External links
- Human CDC20 genome location and CDC20 gene details page in the UCSC Genome Browser.