CDC20

Last updated

CDC20
CDC20.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDC20 , CDC20A, bA276H19.3, p55CDC, cell division cycle 20
External IDs OMIM: 603618; MGI: 1859866; HomoloGene: 37459; GeneCards: CDC20; OMA:CDC20 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

991

107995

Ensembl

ENSG00000117399

ENSMUSG00000006398

UniProt

Q12834

Q9JJ66

RefSeq (mRNA)

NM_001255

NM_023223

RefSeq (protein)

NP_001246

NP_075712

Location (UCSC) Chr 1: 43.36 – 43.36 Mb Chr 4: 118.29 – 118.29 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene [5] [6] 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.

Contents

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 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. [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 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. [35]

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. [36]

Related Research Articles

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Anaphase</span> Stage of a cell division

Anaphase is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes are moved to opposite poles of the cell. Chromosomes also reach their overall maximum condensation in late anaphase, to help chromosome segregation and the re-formation of the nucleus.

<span class="mw-page-title-main">Telophase</span> Final stage of a cell division for eukaryotic cells both in mitosis and meiosis

Telophase is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized. Telophase accounts for approximately 2% of the cell cycle's duration.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

<span class="mw-page-title-main">BUB1</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene.

<span class="mw-page-title-main">MAD2L1</span> Protein-coding gene in the species Homo sapiens

Mitotic spindle assembly checkpoint protein MAD2A is a protein that in humans is encoded by the MAD2L1 gene.

<span class="mw-page-title-main">CDC27</span> Protein-coding gene in humans

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 gene.

<span class="mw-page-title-main">CDC16</span> Protein-coding gene in humans

Cell division cycle protein 16 homolog is a protein that in humans is encoded by the CDC16 gene.

<span class="mw-page-title-main">BUB3</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.

<span class="mw-page-title-main">ANAPC7</span> Protein-coding gene in the species Homo sapiens

Anaphase-promoting complex subunit 7 is an enzyme that in humans is encoded by the ANAPC7 gene. Multiple transcript variants encoding different isoforms have been found for this gene.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

Cdc14 and Cdc14 are a gene and its protein product respectively. Cdc14 is found in most of the eukaryotes. Cdc14 was defined by Hartwell in his famous screen for loci that control the cell cycle of Saccharomyces cerevisiae. Cdc14 was later shown to encode a protein phosphatase. Cdc14 is dual-specificity, which means it has serine/threonine and tyrosine-directed activity. A preference for serines next to proline is reported. Many early studies, especially in the budding yeast Saccharomyces cerevisiae, demonstrated that the protein plays a key role in regulating late mitotic processes. However, more recent work in a range of systems suggests that its cellular function is more complex.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

<span class="mw-page-title-main">APC/C activator protein CDH1</span> Fungal protein found in Saccharomyces cerevisiae S288c

Cdh1 is one of the substrate adaptor proteins of the anaphase-promoting complex (APC) in the budding yeast Saccharomyces cerevisiae. Functioning as an activator of the APC/C, Cdh1 regulates the activity and substrate specificity of this ubiquitin E3-ligase. The human homolog is encoded by the FZR1 gene, which is not to be confused with the CDH1 gene.

Clb5 and Clb6 are B-type, S-phase cyclins in yeast that assist in cell cycle regulation. Clb5 and Clb6 bind and activate Cdk1, and high levels of these cyclins are required for entering S-phase. S-phase cyclin binding to Cdk1 directly stimulates DNA replication as well as progression to the next phase of the cell cycle.

Mitotic exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

<span class="mw-page-title-main">Motifs targeted by APC/C</span>

The anaphase- promoting complex or cyclosome (APC/C) is a highly specific ubiquitin protein ligase responsible for triggering events of late mitosis. In early mitosis, Cdc20 levels rise and APC/C binds to form active APC/CCdc20. This then leads to the destruction of mitotic cyclins, securin, and other proteins to trigger chromosome separation in anaphase. In early anaphase, Cdk1 is inactivated, leading to the activation of Cdh1, the other activator subunit of APC/C. This then triggers the degradation of Cdc20 and leads to the activation of APC/CCdh1 through G1 to suppress S- phase cyclin-Cdk activity. At the end of G1, APC/CCdh1 is inactivated and S- phase and mitotic cyclins gets reaccumulate as the cell progresses to S phase.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000006398 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Weinstein J, Jacobsen FW, Hsu-Chen J, Wu T, Baum LG (May 1994). "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. doi:10.1128/MCB.14.5.3350. PMC   358701 . PMID   7513050.
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  30. ↑ Fang G, Yu H, Kirschner MW (June 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. doi:10.1101/gad.12.12.1871. ISSN   0890-9369. PMC   316912 . PMID   9637688.
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  33. ↑ Kraft C, Vodermaier HC, Maurer-Stroh S, Eisenhaber F, Peters JM (May 2005). "The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates". Mol. Cell. 18 (5): 543–53. doi: 10.1016/j.molcel.2005.04.023 . PMID   15916961.
  34. 1 2 3 Morgan DL (2007). The cell cycle: principles of control. London: Published by New Science Press in association with Oxford University Press. ISBN   978-0-87893-508-6.
  35. ↑ Yu H (July 2007). "Cdc20: a WD40 activator for a cell cycle degradation machine". Mol. Cell. 27 (1): 3–16. doi: 10.1016/j.molcel.2007.06.009 . PMID   17612486.
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