CDC20 explained

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene[1] [2] in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

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.[3]

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.[4] Hartwell found mutants that did not enter anaphase and thus could not complete mitosis; this phenotype could be traced back to the CDC20 gene.[5] 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.[6] [7]

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 interact with:

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.[28] In fact, it is thought that CDC20 and Cdh1 (see below) are receptors for the KEN-box and D-box motifs on substrates.[29] 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.[30] 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.[30]

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.[30]

Spindle assembly checkpoint

CDC20 is also a part of, and regulated by, the spindle assembly checkpoint (SAC). This checkpoint ensures that anaphase proceeds only when the centromeres of all sister chromatids lined up on the metaphase plate are properly attached to microtubules. The checkpoint is held active by any unattached centromere; only when all centromeres are attached will anaphase commence. The APC/CCdc20 is an important target of the SAC, which consists of several different proteins, including Mad2, Mad3(BubR1), and Bub3. In fact, these three proteins, together with CDC20, likely form the mitotic checkpoint complex (MCC), which inhibits APC/CCdc20 so that anaphase cannot begin prematurely. Moreover, Bub1 phosphorylates and thus inhibits CDC20 directly, while in yeast Mad2 and Mad3, when bound to CDC20, trigger its autoubiquitination.[31]

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 tumor size, histological grade (the abnormality of the cells), and metastases to the lymph nodes. In colorectal cancer and non-small-cell lung carcinoma, it is associated with cancer stage, and thus has been proposed as a biomarker to help predict the prognosis for people with either cancer.[32]

Further reading

Notes and References

  1. Weinstein J, Jacobsen FW, Hsu-Chen J, Wu T, Baum LG . A novel mammalian protein, p55CDC, present in dividing cells is associated with protein kinase activity and has homology to the Saccharomyces cerevisiae cell division cycle proteins Cdc20 and Cdc4 . Mol Cell Biol . 14 . 5 . 3350–63 . May 1994 . 7513050 . 358701 . 10.1128/MCB.14.5.3350.
  2. Weinstein J . Cell cycle-regulated expression, phosphorylation, and degradation of p55Cdc. A mammalian homolog of CDC20/Fizzy/slp1 . J Biol Chem . 272 . 45 . 28501–11 . December 1997 . 9353311 . 10.1074/jbc.272.45.28501 . free .
  3. Web site: Entrez Gene: CDC20 cell division cycle 20 homolog (S. cerevisiae).
  4. Hartwell LH, Culotti J, Reid B . Genetic Control of the Cell-Division Cycle in Yeast, I. Detection of Mutants . Proc. Natl. Acad. Sci. U.S.A. . 66 . 2 . 352–9 . June 1970 . 5271168 . 283051 . 10.1073/pnas.66.2.352 . 1970PNAS...66..352H . free .
  5. Hartwell LH, Mortimer RK, Culotti J, Culotti M . Genetic Control of the Cell Division Cycle in Yeast: V. Genetic Analysis of cdc Mutants . Genetics . 74 . 2 . 267–286 . June 1973 . 10.1093/genetics/74.2.267 . 17248617 . 1212945 .
  6. King RW, Peters JM, Tugendreich S, Rolfe M, Hieter P, Kirschner MW . 16958690 . A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B . Cell . 81 . 2 . 279–88 . April 1995 . 7736580 . 10.1016/0092-8674(95)90338-0 . free .
  7. Sudakin V, Ganoth D, Dahan A, Heller H, Hershko J, Luca FC, Ruderman JV, Hershko A . The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis . Mol. Biol. Cell . 6 . 2 . 185–97 . February 1995 . 7787245 . 275828 . 10.1091/mbc.6.2.185 .
  8. Fang G . Checkpoint Protein BubR1 Acts Synergistically with Mad2 to Inhibit Anaphase-promoting Complex . Mol. Biol. Cell . 13 . 3 . 755–66 . March 2002 . 11907259 . 99596 . 10.1091/mbc.01-09-0437 . 1059-1524 .
  9. Wu H, Lan Z, Li W, Wu S, Weinstein J, Sakamoto KM, Dai W . p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase . Oncogene . 19 . 40 . 4557–62 . September 2000 . 11030144 . 10.1038/sj.onc.1203803 . 23544995 . 0950-9232 .
  10. Sudakin V, Chan GK, Yen TJ . Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2 . J. Cell Biol. . 154 . 5 . 925–36 . September 2001 . 11535616 . 2196190 . 10.1083/jcb.200102093 . 0021-9525 .
  11. Skoufias DA, Andreassen PR, Lacroix FB, Wilson L, Margolis RL . Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints . . 98 . 8 . 4492–7 . April 2001 . 11274370 . 31862 . 10.1073/pnas.081076898 . 2001PNAS...98.4492S . free .
  12. Vodermaier HC, Gieffers C, Maurer-Stroh S, Eisenhaber F, Peters JM . 5942532 . TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1 . Curr. Biol. . 13 . 17 . 1459–68 . September 2003 . 12956947 . 10.1016/S0960-9822(03)00581-5 . 0960-9822 . free . 2003CBio...13.1459V .
  13. Nilsson J, Yekezare M, Minshull J, Pines J . The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction . Nat. Cell Biol. . 10 . 12 . 1411–20 . December 2008 . 18997788 . 2635557 . 10.1038/ncb1799 .
  14. Kallio MJ, Beardmore VA, Weinstein J, Gorbsky GJ . Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells . J. Cell Biol. . 158 . 5 . 841–7 . September 2002 . 12196507 . 2173153 . 10.1083/jcb.200201135 . 0021-9525 .
  15. Kallio M, Weinstein J, Daum JR, Burke DJ, Gorbsky GJ . 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 . June 1998 . 9628895 . 2132789 . 10.1083/jcb.141.6.1393 . 0021-9525 .
  16. D'Angiolella V, Mari C, Nocera D, Rametti L, Grieco D . The spindle checkpoint requires cyclin-dependent kinase activity . Genes Dev. . 17 . 20 . 2520–5 . October 2003 . 14561775 . 218146 . 10.1101/gad.267603 . 0890-9369 .
  17. Wassmann K, Benezra R . Mad2 transiently associates with an APC/p55Cdc complex during mitosis . . 95 . 19 . 11193–8 . September 1998 . 9736712 . 21618 . 10.1073/pnas.95.19.11193 . 1998PNAS...9511193W . 0027-8424 . free .
  18. Kramer ER, Gieffers C, Hölzl G, Hengstschläger M, Peters JM . 17181162 . Activation of the human anaphase-promoting complex by proteins of the CDC20/Fizzy family . Curr. Biol. . 8 . 22 . 1207–10 . November 1998 . 9811605 . 10.1016/S0960-9822(07)00510-6 . 0960-9822 . free . 1998CBio....8.1207K .
  19. Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Hatakeyama M . 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 . February 2000 . 10679238 . 10.1006/bbrc.2000.2167 . 0006-291X .
  20. Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK . 25403043 . E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC/C(Cdh1) . Nat. Cell Biol. . 4 . 5 . 358–66 . May 2002 . 11988738 . 10.1038/ncb785 . 1465-7392 .
  21. Yoon YM, Baek KH, Jeong SJ, Shin HJ, Ha GH, Jeon AH, Hwang SG, Chun JS, Lee CW . WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase . FEBS Lett. . 575 . 1–3 . 23–9 . September 2004 . 15388328 . 10.1016/j.febslet.2004.07.089 . 21762011 . 0014-5793 . free .
  22. Zhang Y, Lees E . 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 . August 2001 . 11438673 . 87243 . 10.1128/MCB.21.15.5190-5199.2001 . 0270-7306 .
  23. Sihn CR, Suh EJ, Lee KH, Kim TY, Kim SH . p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells . Cancer Lett. . 201 . 2 . 203–10 . November 2003 . 14607335 . 10.1016/S0304-3835(03)00465-8 . 0304-3835 .
  24. Luo X, Fang G, Coldiron M, Lin Y, Yu H, Kirschner MW, Wagner G . 1721494 . Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20 . Nat. Struct. Biol. . 7 . 3 . 224–9 . March 2000 . 10700282 . 10.1038/73338 . 1072-8368 .
  25. Sironi L, Melixetian M, Faretta M, Prosperini E, Helin K, Musacchio A . Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint . EMBO J. . 20 . 22 . 6371–82 . November 2001 . 11707408 . 125308 . 10.1093/emboj/20.22.6371 . 0261-4189 .
  26. Fang G, Yu H, Kirschner MW . 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 . June 1998 . 9637688 . 316912 . 10.1101/gad.12.12.1871 . 0890-9369 .
  27. Privette LM, Weier JF, Nguyen HN, Yu X, Petty EM . Loss of CHFR in Human Mammary Epithelial Cells Causes Genomic Instability by Disrupting the Mitotic Spindle Assembly Checkpoint . Neoplasia . 10 . 7 . 643–52 . July 2008 . 18592005 . 2435002 . 10.1593/neo.08176.
  28. Vodermaier HC . 11277828 . Cell cycle: Waiters serving the Destruction machinery . Curr. Biol. . 11 . 20 . R834–7 . October 2001 . 11676939 . 10.1016/S0960-9822(01)00498-5 . free . 2001CBio...11.R834V .
  29. Kraft C, Vodermaier HC, Maurer-Stroh S, Eisenhaber F, Peters JM . The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates . Mol. Cell . 18 . 5 . 543–53 . May 2005 . 15916961 . 10.1016/j.molcel.2005.04.023 . free .
  30. Book: Morgan DL . The cell cycle: principles of control . Published by New Science Press in association with Oxford University Press . London . 2007 . 978-0-87893-508-6 .
  31. Yu H . Cdc20: a WD40 activator for a cell cycle degradation machine . Mol. Cell . 27 . 1 . 3–16 . July 2007 . 17612486 . 10.1016/j.molcel.2007.06.009 . free .
  32. 10.1146/annurev-cancerbio-030419-033541. free. Deregulation of Chromosome Segregation and Cancer. 2020. Curtis. Natalie L.. Ruda. Gian Filippo. Brennan. Paul. Bolanos-Garcia. Victor M.. Annual Review of Cancer Biology. 4. 257–278.

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