238:
Eleven core APC subunits have been found in vertebrates versus thirteen in yeast. Activator subunits bind to APC at varying stages of the cell cycle to control its ubiquitination activity, often by directing APC to target substrates destined for ubiquitination. The specificity of APC ligases is proposed to be controlled by the incorporation of specificity factors into the ligase complex, instead of substrate phosphorylation. i.e.: The subunit, CDC20 allows APC to degrade substrates such as anaphase inhibitors (Pdsp1) at the beginning of anaphase, on the other hand when CDC20 is substituted for specificity factor Hct1, APC degrades a different set of substrates, particularly mitosis cyclins in late anaphase. Activators CDC20 and Cdh1 are of particular significance and are the most widely studied and familiar of the APC/C subunits.
133:
27:
283:
which is created in response to TGFβ signalling. Because of its interaction with Cdh1 in particular, it has a potential role in determining affinity between APC and its activators Cdc20 and Cdh1. A study suggests that TGF-β-induced Cdc27 phosphorylation enhances interaction between cdc27 and Cdh1–which is directly involved in activating APC. CDC27 can serve as a vehicle through which TGFβ signalling can activate APC. Induced CDC27 hyperphosphorylation by TGFβ showed elevated APC activity.
251:
suggested that variations in these WD40 domains result in varying substrate specificity, which is confirmed by recent results suggesting that different APC substrates can directly and specifically bind to Cdc20 and Cdh1/Hct1 Ultimately, the specificity differences are responsible for the timing of the destruction of several APC targets during mitosis. With CDC20 targeting a few major substrates at metaphase and Cdh1 targeting a broader range of substrates towards late mitosis and G1.
270:
binding to APC from S to M phase. With destruction of M-Cdk, release of CDC20 from the APC and binding of Cdh1 can now occur, allowing APC activity to continue on during G1 entry. While Cdh1 recognizes M and S cyclins, allowing for their destruction until the entire cell commits to proceed to a new cycle, it does not recognize G1/S cyclins, and during G1/S phase, their cyclin activity can rise unhindered and phosphorylate and thus inactivating Cdh1 and therefore APC.
372:, a process known as chromosome biorientation. When all kinetochores are properly attached, the spindle checkpoint is silenced and the APC/C can become active. M-Cdks phosphorylate subunits on the APC/C that promote binding to Cdc20. Securin and M cyclins (cyclin A and cyclin B) are then targeted by APC/C for degradation. Once degraded, separin is released, cohesin is degraded and sister chromatids are prepared to move to their respective poles for anaphase.
412:, to grow and produce factors necessary for the next cell cycle. Entry into another round of mitosis is prevented by inhibiting Cdk activity. While different processes are responsible for this inhibition, an important one is activation of the APC/C by Cdh1. This continued activation prevents the accumulation of cyclin that would trigger another round of mitosis and instead drives exit from mitosis.
262:, and Apc5, mainly provide scaffolding and support to mediate other protein-protein interactions. Cdc27 and Cdc23 have been shown to support the binding of Cdc20 and Cdh1, as mutations in key residues of these subunits led to increased dissociation of the activators. Apc10/Doc1, has been shown to promote substrate binding by mediating their interactions with Cdh1 and Cdc20.
242:
transfer of ubiquitin to an active site in E2. In addition to the catalytic functionality, other core proteins of the APC are composed multiple repeat motifs with the main purpose of providing molecular scaffold support. These include Apc1, the largest subunit which contains 11 tandem repeats of 35–40 amino acid sequences, and Apc2, which contains three
296:(RNAi). Results suggest that they may mediate activity of the entire complex via different mechanisms at different sites. In further drosophila studies, Cdk16 and cdk23 appear to be activated via phosphorylation by Polo-like kinase 1 (Plk1) and its fission yeast counterpart, appear to bind particularly to Cdc23.
269:
Evidence shows that APC3 and APC7 serve to recruit Cdh1 to the anaphase-promoting complex. This further supports that Cdh1 is responsible for maintaining APC activity during G1. Cdh1 does not require APC to be phosphorylated in order to bind, in fact, phosphorylation of Cdh1 by Cdks prevents it from
250:
and WD40 repeats 1. C-termini regions of CDC20 and Cdh1 have a WD40 domain that is suggested to form a binding platform that binds APC substrates, thus contributing to APCs ability to target these substrates, although the exact mechanism through which they increase APC activity is unknown. It is also
347:
propeller region on the APC activators. It is important to note that the conserved area of the propeller of Cdh1 is much larger than that of Cdc20, allowing Cdh1 to have a broader substrate specificity, consistent with the fact that APC/C also activates APC-mediated destruction of KEN box containing
420:
transition. A key difference to note is that while binding of Cdc20 to APC/C is dependent on phosphorylation of APC/C by mitotic Cdks, binding of Cdh1 is not. Thus, as APC becomes inactivated during metaphase due to dephosphorylation resulting from inactive mitotic Cdks, Cdh1 is able to immediately
415:
In the beginning of the cell cycle Cdh1 is phosphorylated by M-Cdk, preventing it from attaching to APC/C. APC/C is then free to attach to Cdc20 and usher the transition from metaphase to anaphase. As M-Cdk gets degraded later in mitosis, Cdc20 gets released and Cdh1 can bind to APC/C, keeping it
282:
One of the subunits that exhibit the TPR motif, CDC27 has been identified to interact with mitotic checkpoint proteins such as Mad2, p55CDC and BUBR1, suggesting that it may have involvement in the timing of M phase. Evidence shows that CDC27 is involved in a ternary complex with SMAD2/3 and Cdh1,
265:
In particular, CDC20 (also known as p55CDC, Fizzy, or Slp1) inactivates CDK1 via ubiquitination of B-type cyclins. This results in activation of Cdh1(a.k.a. Fizzy-related, Hct1, Ste9, or Srw1), which interacts with APC during late mitosis and G1/G0. Cdh1 is inactivated via phosphorylation during S,
136:
M–Cdk activity promotes the events of early mitosis, resulting in the metaphase alignment of sister chromatids on the spindle. M–Cdk activity also promotes the activation of APCCdc20, which triggers anaphase and mitotic exit by stimulating the destruction of regulatory proteins, such as securin and
480:
Regulation of APC/C activity towards metaphase substrates like securin and cyclin B may be a result of intracellular localization. It is hypothesized that spindle checkpoint proteins that inhibit APC/C only associate with a subset of the Cdc20 population localized near the mitotic spindle. In this
468:
From these early observations, it has been confirmed that in G2 and early mitosis, Emi1 binds and inhibits Cdc20 by preventing its association with APC substrates. Cdc20 can still be phosphorylated and bind to APC/C, but bound Emi1 blocks Cdc20's interaction with APC targets. Emi1 association with
299:
The complex is understood to be regulated by activators CDC20 and Cdh1 during mitosis. Their role in degradation for cyclin B is demonstrated by a screen of
Saccharomyces cerevisiae mutants defective for cyclin B degradation, which were found to have mutations in CDC16 and CDC23 genes. Mutants for
291:
CDC23, another TPR subunit interacts with SWM1, binding to the D-box of CLB2. Based upon hybrid assays in vivo and co-immunoprecipitation in vitro, it is suggested that Cdc16p, Cdc23p and Cdc27p (analogs in
Sacchyromyces cerevisiae) interact and form a macromolecular complex. Their common theme of
273:
The subunit Apc15 plays an important role in APC/C activation following the bi-orientation of sister chromatids across the metaphase plate. When kinetochores are unattached to spindles, mitotic checkpoint complexes (MCC) and inhibit APC. In the absence of Apc15, MCCs and Cdc20 remain locked on the
391:
loop. While activation of APC/C requires M-Cdk, the complex is also responsible for breaking the cyclin to deactivate M-CdK. This means that APC/C fosters its own deactivation. It is possible that this negative feedback is the backbone of Cdk activity controlled by M and S cyclin concentration
355:
Although Cdc20 and Cdh1 may serve as D and KEN box receptors, the low affinity of these co-activator–substrate interactions suggests that it is unlikely that the co-activators alone are sufficient to confer high-affinity substrate binding to the APC/C and APC/C. Consequently, core APC/C subunits,
237:
There is not a vast amount of extensive investigation on APC/C subunits, which serve mostly as adaptors. Studies of APC subunits are mainly conducted in yeast, and studies show that the majority of yeast APC subunits are also present in vertebrates, this suggests conservation across eukaryotes.
351:
Many APC substrates contain both D and KEN boxes, with their ubiquitylation by either APC/C or APC/C dependent on both sequences, yet some substrates contain only either a D box or a KEN box, in one or multiple copies. Having two distinct degradation sequences creates a high level of substrate
241:
The catalytic core of the APC/C consists of the cullin subunit Apc2 and RING H2 domain subunit Apc11. These two subunits catalyze ubiquitination of substrates when the C-terminal domain of Apc2 forms a tight complex with Apc11. RING/APc11 binds to the E2-ubiquitin conjugate that catalyzes the
464:
APC/C inactivation during early stages of the cell cycle is partially achieved by the protein Emi1. Initial experiments have shown that addition of Emi1 to
Xenopus cycling extracts can prevent the destruction of endogenous cyclin A, cyclin B, and mitotic exit, suggesting that Emi1 is able to
208:
are the two activators of particular importance to the cell cycle. These proteins target the APC/C to specific sets of substrates at different times in the cell cycle, thus driving it forward. The APC/C also plays an integral role in the maintenance of chromatin metabolism, particularly in
456:(Cdc7) activity, which promotes activation of replication origins. APCCdh1 is thought to target Dbf4 for destruction. This could provide an answer as to how Cdc7 is activated at the beginning of a new cell cycle. Its activity likely corresponds to the inactivation of APC/C by G/S cyclins.
383:
and securin are not degraded until metaphase. The molecular basis of the delay is unknown, but is believed to involve the key to the correct timing of anaphase initiation. In animal cells the spindle checkpoint system contributes to the delay if it needs to correct the bi-orientation of
477:βTrCP binding site makes it a target for SCF, leading to its subsequent destruction in prometaphase. Emi1's destruction leads APC/CCdc20 activation, allowing for the destruction of cyclin A in early mitosis. Emi1 levels begin to rise again in G, which help inhibit APC/C.
356:
like Apc10, contribute towards substrate association as well. In APC/C constructs lacking the Apc10/Doc1 subunit, substrates like Clb2 are unable to associate with APC–Cdh1, while addition of purified Doc1 to the APC–Cdh1 construct restores the substrate binding ability.
444:, APC is responsible for the degradation of various proteins that promote proper cell cycle progression. Geminin is a protein that binds to Cdt1 which prevents its binding to the origin recognition complex (ORC). APC targets geminin for ubiquitination throughout G
384:
chromosomes. Though how the spindle checkpoint system inhibits cyclin B and securin destruction while allowing cyclin A to be degraded is unknown. The delay may also be explained by unknown interactions with regulators, localization and phosphorylation changes.
348:
substrates. The D box further enhances protein degradation, for Lysine residues in close proximity to the D box serve as targets of ubiquitylation. It has been found that a Lys residue immediately C-terminal to the D box can function as a ubiquitin acceptor.
228:
The critical substrates of the APC/C appear to be securin and the B type cyclins. This is conserved between mammals and yeast. In fact, yeast are viable in the absence of the APC/C if the requirement for targeting these two substrates is eliminated.
336:. The last amino acid position in the Ken-box is highly variable. Though it has been shown that mutations in the sequences do inhibit destruction of the proteins "in vivo", there is still much to learn about how proteins are targeted by the APC/C.
30:
The anaphase-promoting complex (APC) is a large protein complex containing 11–13 subunits, including a RING subunit (Apc11) and a cullin (Apc2). APC activity requires association with activator subunits (Cdc20 or Cdh1) that contribute to substrate
465:
counteract the activity of the APC. Furthermore, depletion of Emi1 in somatic cells leads to the lack of accumulation of cyclin B. The lack of Emi1 likely leads to a lack of inhibition of the APC preventing cyclin B from accumulating.
1323:"Mutations in mákos, a Drosophila gene encoding the Cdc27 subunit of the anaphase promoting complex, enhance centrosomal defects in polo and are suppressed by mutations in twins/aar, which encodes a regulatory subunit of PP2A"
352:
specificity on the APC/C, with APC/C being more dependent on the D box and APC/C more dependent on the KEN box. For example, APC/C is capable of ubiquitylating KEN box-only-containing substrates like Tome-1 and
Sororin.
177:, sister chromatids are linked by intact cohesin complexes. When securin undergoes ubiquitination by the APC/C and releases separase, which degrades cohesin, sister chromatids become free to move to opposite
469:
Cdc20 allows for the stabilization of various cyclins throughout S and G2 phase, but Emi1's removal is essential for progression through mitosis. Thus, in late prophase, Emi1 is phosphorylated by
375:
It is likely that, in animal cells, at least some of the activation of APC/C occurs early in the cell cycle (prophase or prometaphase) based on the timing of the degradation of its substrates.
308:
APC/C substrates have recognition amino acid sequences that enable the APC/C to identify them. The most common sequence is known as the destruction box or D-box. APC/C brings together an E2
274:
APC/C preventing its activity once the spindle checkpoint requirements are met. Apc15 mediates the turnover of Cdc20 and MCCs to provide information on the attachment state of kinetochores.
2767:
137:
cyclins, that govern these events. By promoting cyclin destruction and thus Cdk inactivation, APCCdc20 also triggers activation of APCCdh1, thereby ensuring continued APC activity in G
254:
Most notably, 4 subunits of yeast APC/C consist almost entirely of multiple repeats of the 34 amino acid tetratricopeptide residue (TPR) motif. These TPR subunits, Cdc16,
2760:
1284:"The dynamic localisation of the Drosophila APC/C: evidence for the existence of multiple complexes that perform distinct functions and are differentially localised"
101:
in cell biology. Once perceived as a system exclusively involved in removing damaged protein from the cell, ubiquitination and subsequent protein degradation by the
2753:
1554:"Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1"
448:, keeping its levels low. This allows Cdt1 to carry out its function during pre-RC assembly. When APC becomes inactive due to phosphorylation of Cdh1 by G
1643:
Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK (May 2002). "E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1)".
781:
Castro A, Bernis C, Vigneron S, Labbé JC, Lorca T (January 2005). "The anaphase-promoting complex: a key factor in the regulation of cell cycle".
2666:
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453:
19:
This article is about the cell-cycle regulatory complex, APC/C. For the tumor suppressor APC, in which mutations lead to colon cancer, see
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bind to APC/C, taking Cdc20's place. Cdc20 is also a target of APC/C, ensuring that APC/C is shut down. APC/C then continues working in G
2682:
2501:
2375:
1606:
Visintin R, Prinz S, Amon A (October 1997). "CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis".
570:
2414:
2131:
2025:
2606:
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manner, cyclin A can be degraded while cyclin B and securin are degraded only once sister chromatids have achieved bi-orientation.
259:
255:
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554:
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TPR is suggested to mediate these interactions. As for Cdc27 and Cdc16 in drosophila, their functions have been tested via
2520:
2071:
2659:
429:/S cyclins are not substrates of APC/C and therefore accumulate throughout this phase and phosphorylate Cdh1. By late G
404:
Upon completion of mitosis, it is important that cells (except for embryonic ones) go through a growth period, known as
2342:
328:. The Ken-box is another motif of importance. Its sequence should resemble the one that follows: KENXXXN, where K is
1832:
1126:"APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment"
668:
542:
2745:
312:
and the D-box rather than being an intermediate covalent carrier. The D-box should have a version of the following
2621:
2626:
684:
Thornton BR, Toczyski DP (December 2003). "Securin and B-cyclin/CDK are the only essential targets of the APC".
2718:
2652:
2616:
2510:
2633:
2459:
2335:
1825:
309:
205:
2141:
1411:
King RW, Deshaies RJ, Peters JM, Kirschner MW (December 1996). "How proteolysis drives the cell cycle".
924:"Structure of an APC3-APC16 complex: insights into assembly of the anaphase-promoting complex/cyclosome"
153:
by tagging specific proteins for degradation. The three major targets for degradation by the APC/C are
2601:
2596:
2479:
2454:
2439:
2399:
2282:
1985:
1283:
979:"Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition"
339:
Once bound to APC/C, Cdc20 and Cdh1 serve as D and KEN box receptors for various APC substrates. Kraft
20:
1802:
437:/S cyclins have accumulated and phosphorylated Cdh1 to inactivate the APC/C until the next metaphase.
2713:
2591:
2515:
2474:
2434:
2424:
2419:
2404:
2384:
1980:
1975:
1970:
1965:
1960:
1955:
1950:
1945:
1940:
2784:
2679:
2484:
2409:
2394:
2366:
1806:
1505:"Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex"
490:
247:
2464:
2444:
2429:
2389:
1932:
473:, Plk. Plk is activated during early mitosis by Cdk1 activity, and its phosphorylation of Emi1's
186:
110:
1464:"The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates"
826:"Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC"
2708:
2581:
2489:
2469:
2449:
1077:"TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1"
2611:
2327:
2264:
2015:
922:
Yamaguchi M, Yu S, Qiao R, Weissmann F, Miller DJ, VanderLinden R, et al. (April 2015).
875:"Insights into anaphase promoting complex TPR subdomain assembly from a CDC26-APC6 structure"
1812:
1364:"Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae"
132:
120:, which also uncovered its secondary structure. This finding could improve understanding of
93:) and their key role in eukaryotic cell-cycle regulation that established the importance of
2703:
2539:
1615:
1420:
1184:"Phosphorylation of the anaphase-promoting complex/Cdc27 is involved in TGF-beta signaling"
609:
2644:
8:
2821:
2734:
1813:
3D electron microscopy structures of
Anaphase-promoting complex at the EM Data Bank(EMDB)
1752:"Genomic evolution and complexity of the Anaphase-promoting Complex (APC) in land plants"
246:
repeats of approximately 130 amino acids total. The major motifs in APC subunits include
106:
1619:
1424:
738:
Philosophical
Transactions of the Royal Society of London. Series B, Biological Sciences
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G2 and early M phase. During these points in the cycle, it is not able to be assembled.
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1125:
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923:
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709:
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597:
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inhibits the APC/C until all sister-kinetochores are attached to opposite poles of the
365:
83:
26:
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1681:
1578:
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1504:
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978:
850:
825:
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2775:
2272:
1783:
1750:
Lima M, Eloy NB, Pegoraro C, Sagit R, Rojas C, Bretz T, et al. (November 2010).
1738:
1703:
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1631:
1583:
1526:
1485:
1436:
1393:
1344:
1303:
1264:
1215:
1155:
1098:
1075:
Vodermaier HC, Gieffers C, Maurer-Stroh S, Eisenhaber F, Peters JM (September 2003).
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904:
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293:
47:
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977:, McCormack EA, Au SW, Paul A, Willison KR, Harper JW, Barford D (February 2003).
1627:
1480:
1463:
1379:
369:
222:
2586:
841:
658:
654:
452:/S cyclins, geminin activity is increased again. Additionally, Dbf4 stimulates
182:
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have shown that the substrates' D boxes bind directly to the highly conserved
2841:
2695:
2211:
1768:
974:
1682:"Whose end is destruction: cell division and the anaphase-promoting complex"
1569:
1462:
Kraft C, Vodermaier HC, Maurer-Stroh S, Eisenhaber F, Peters JM (May 2005).
1299:
1200:
734:"Structural insights into anaphase-promoting complex function and mechanism"
2233:
1787:
1742:
1707:
1698:
1664:
1587:
1530:
1503:
Reimann JD, Freed E, Hsu JY, Kramer ER, Peters JM, Jackson PK (June 2001).
1489:
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1307:
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1159:
1102:
1061:
1012:
994:
957:
908:
859:
802:
794:
767:
749:
705:
639:
178:
1635:
1440:
1397:
1268:
1124:
Mansfeld J, Collin P, Collins MO, Choudhary JS, Pines J (September 2011).
1043:
1026:
Kramer ER, Scheuringer N, Podtelejnikov AV, Mann M, Peters JM (May 2000).
300:
CDC27, CDC23 and CDC 27 all resulted in a cell-cycle arrest at metaphase.
2254:
2223:
873:
Wang J, Dye BT, Rajashankar KR, Kurinov I, Schulman BA (September 2009).
653:
Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P, eds. (2002).
474:
344:
194:
98:
90:
79:
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1074:
621:
598:"Molecular architecture and mechanism of the anaphase-promoting complex"
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102:
55:
51:
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890:
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Chang LF, Zhang Z, Yang J, McLaughlin SH, Barford D (September 2014).
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1907:
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117:
94:
1717:"The anaphase-promoting complex: it's not just for mitosis any more"
1172:"Entrez Gene: CDC27 cell division cycle 27 homolog (S. cerevisiae)".
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697:
571:"Scientists map one of most important proteins in life – and cancer"
165:, a protease, when degraded. Separase then triggers the cleavage of
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380:
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In 2014, the APC/C was mapped in 3D at a resolution of less than a
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82:. Other parts of the APC/C have unknown functions but are highly
2312:
2219:
2192:
1851:
1028:"Mitotic regulation of the APC activator proteins CDC20 and CDH1"
321:
190:
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for degradation, resulting in the inactivation of M-CDK (mitotic
166:
154:
75:
59:
1235:"Cdc16p, Cdc23p and Cdc27p form a complex essential for mitosis"
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2049:
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1995:
1990:
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243:
158:
121:
67:
63:
2357:
1233:
Lamb JR, Michaud WA, Sikorski RS, Hieter PA (September 1994).
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2126:
2121:
2010:
2005:
2000:
201:
824:
Schwab M, Neutzner M, Möcker D, Seufert W (September 2001).
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The APC/C's main function is to trigger the transition from
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2574:
2564:
2155:
2146:
2116:
2095:
2033:
1410:
823:
71:
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Hansen DV, Loktev AV, Ban KH, Jackson PK (December 2004).
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2100:
2090:
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is degraded early in mitosis, supporting the theory, but
105:
is now perceived as a universal regulatory mechanism for
921:
595:
1642:
973:
652:
200:
Unlike the SCF, activator subunits control the APC/C.
1551:
655:"Chapter 17. The Cell Cycle and Programmed Cell Death"
124:
and reveal new binding sites for future cancer drugs.
1749:
1502:
1182:
Zhang L, Fujita T, Wu G, Xiao X, Wan Y (March 2011).
1715:Harper JW, Burton JL, Solomon MJ (September 2002).
1714:
1320:
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to tag S and M cyclins for destruction. However, G
359:
1605:
1181:
58:. The APC/C is a large complex of 11–13 subunit
2839:
1679:
683:
1321:Deak P, Donaldson M, Glover DM (October 2003).
543:"Chapter 3-10: The Anaphase Promoting Complex"
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534:
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549:. London: New Science Press. pp. 48–49.
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217:, and plays a key role in phosphorylation of
454:Cell division cycle 7-related protein kinase
969:
967:
2768:
2754:
2667:
2653:
2350:
2336:
1840:
1826:
503:
181:for anaphase. The APC/C also targets the
2132:Cellular apoptosis susceptibility protein
1805:at the U.S. National Library of Medicine
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1520:
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1002:
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898:
879:Nature Structural & Molecular Biology
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757:
727:
725:
723:
629:
964:
459:
303:
169:, the protein complex that binds sister
131:
25:
1847:
731:
677:
89:It was the discovery of the APC/C (and
2840:
2779:: Phosphoric ester and nitrogen-metal
1680:Zachariae W, Nasmyth K (August 1999).
720:
540:
286:
2749:
2648:
2415:D-alanine—poly(phosphoribitol) ligase
2331:
1821:
547:The Cell Cycle: Principles of Control
395:
109:whose importance approaches that of
54:proteins for degradation by the 26S
1188:The Journal of Biological Chemistry
646:
13:
2555:Von Hippel–Lindau tumor suppressor
1598:
1362:Hartwell LH, Smith D (July 1985).
1251:10.1002/j.1460-2075.1994.tb06752.x
14:
2864:
1796:
663:(4th ed.). Garland Science.
189:) complexes, promoting exit from
2521:Long-chain-fatty-acid—CoA ligase
575:The Institute of Cancer Research
360:Metaphase to anaphase transition
316:sequence: RXXLXXXXN, where R is
1545:
1496:
1455:
1404:
1355:
1314:
1282:Huang JY, Raff JW (July 2002).
1275:
1226:
1175:
1166:
1117:
1068:
1019:
915:
2719:Methylcrotonyl-CoA carboxylase
2617:Carbamoyl phosphate synthetase
2511:Succinyl coenzyme A synthetase
866:
817:
774:
589:
563:
248:tetratricopeptide (TPR) motifs
1:
1558:Molecular Biology of the Cell
1522:10.1016/s0092-8674(01)00361-0
1433:10.1126/science.274.5293.1652
1094:10.1016/s0960-9822(03)00581-5
1032:Molecular Biology of the Cell
660:Molecular Biology of the Cell
496:
277:
16:Cell-cycle regulatory complex
1628:10.1126/science.278.5337.460
1481:10.1016/j.molcel.2005.04.023
928:Journal of Molecular Biology
320:, X is any amino acid, L is
310:ubiquitin-conjugating enzyme
7:
2142:Maturation promoting factor
732:Barford D (December 2011).
484:
232:
221:through destruction of the
127:
10:
2869:
2602:Holocarboxylase synthetase
2597:Argininosuccinate synthase
2570:Anaphase-promoting complex
2283:Postreplication checkpoint
1803:anaphase-promoting+complex
1380:10.1093/genetics/110.3.381
36:Anaphase-promoting complex
21:Adenomatous polyposis coli
18:
2811:
2792:
2727:
2714:Propionyl-CoA carboxylase
2690:
2678:: carbon-carbon ligases (
2634:Glutamate–cysteine ligase
2592:Adenylosuccinate synthase
2529:
2500:
2385:Aminoacyl tRNA synthetase
2374:
2291:
2263:
2210:
2174:
2165:
2109:
2081:
2024:
1931:
1858:
940:10.1016/j.jmb.2014.11.020
416:activated through the M/G
364:As metaphase begins, the
1807:Medical Subject Headings
1769:10.1186/1471-2229-10-254
842:10.1093/emboj/20.18.5165
491:Motifs Targeted by APC/C
1721:Genes & Development
1686:Genes & Development
1570:10.1091/mbc.e04-07-0598
1327:Journal of Cell Science
1300:10.1242/jcs.115.14.2847
1288:Journal of Cell Science
1201:10.1074/jbc.M110.205518
187:cyclin-dependent kinase
111:protein phosphorylation
2709:Acetyl-CoA carboxylase
2582:Glutathione synthetase
2265:Cell cycle checkpoints
1699:10.1101/gad.13.16.2039
795:10.1038/sj.onc.1207973
750:10.1098/rstb.2011.0069
142:
32:
2612:Asparagine synthetase
2516:Acetyl—CoA synthetase
2292:Other cellular phases
2016:CDK-activating kinase
1044:10.1091/mbc.11.5.1555
460:Additional regulation
304:Substrate recognition
135:
29:
2704:Pyruvate carboxylase
2540:Glutamine synthetase
995:10.1093/emboj/cdg084
78:) subunit much like
2822:Magnesium chelatase
2735:Polyketide synthase
1734:10.1101/gad.1013102
1645:Nature Cell Biology
1620:1997Sci...278..460V
1425:1996Sci...274.1652K
1130:Nature Cell Biology
686:Nature Cell Biology
622:10.1038/nature13543
614:2014Natur.513..388C
287:CDC23, CDC16, CDC27
161:. Securin releases
107:signal transduction
2796:: Phosphoric Ester
2278:Spindle checkpoint
2083:P53 p63 p73 family
1333:(Pt 20): 4147–58.
1294:(Pt 14): 2847–56.
541:Morgan DO (2007).
366:spindle checkpoint
173:together. During
143:
50:that marks target
33:
2835:
2834:
2743:
2742:
2642:
2641:
2533:: Carbon-Nitrogen
2325:
2324:
2321:
2320:
2273:Restriction point
1756:BMC Plant Biology
1340:10.1242/jcs.00722
891:10.1038/nsmb.1645
744:(1584): 3605–24.
608:(7518): 388–393.
556:978-0-9539181-2-6
433:, enough of the G
389:negative feedback
387:This initiates a
38:(also called the
2860:
2827:Cobalt chelatase
2815:: Nitrogen-Metal
2770:
2763:
2756:
2747:
2746:
2669:
2662:
2655:
2646:
2645:
2545:Ubiquitin ligase
2352:
2345:
2338:
2329:
2328:
2172:
2171:
1842:
1835:
1828:
1819:
1818:
1791:
1781:
1771:
1746:
1736:
1727:(17): 2179–206.
1711:
1701:
1676:
1639:
1592:
1591:
1581:
1549:
1543:
1542:
1524:
1500:
1494:
1493:
1483:
1459:
1453:
1452:
1419:(5293): 1652–9.
1408:
1402:
1401:
1391:
1359:
1353:
1352:
1342:
1318:
1312:
1311:
1279:
1273:
1272:
1262:
1239:The EMBO Journal
1230:
1224:
1223:
1213:
1203:
1194:(12): 10041–50.
1179:
1173:
1170:
1164:
1163:
1153:
1121:
1115:
1114:
1096:
1072:
1066:
1065:
1055:
1023:
1017:
1016:
1006:
983:The EMBO Journal
971:
962:
961:
951:
919:
913:
912:
902:
870:
864:
863:
853:
830:The EMBO Journal
821:
815:
814:
778:
772:
771:
761:
729:
718:
717:
681:
675:
674:
650:
644:
643:
633:
593:
587:
586:
584:
582:
567:
561:
560:
538:
471:Polo-like kinase
294:RNA interference
48:ubiquitin ligase
2868:
2867:
2863:
2862:
2861:
2859:
2858:
2857:
2838:
2837:
2836:
2831:
2807:
2788:
2774:
2744:
2739:
2723:
2686:
2673:
2643:
2638:
2525:
2504:: Carbon-Sulfur
2496:
2378:: Carbon-Oxygen
2370:
2361:: CO CS and CN
2356:
2326:
2317:
2307:
2287:
2259:
2206:
2201:
2187:
2167:
2161:
2105:
2077:
2020:
1927:
1854:
1846:
1799:
1794:
1692:(16): 2039–58.
1614:(5337): 460–3.
1601:
1599:Further reading
1596:
1595:
1564:(12): 5623–34.
1550:
1546:
1501:
1497:
1460:
1456:
1409:
1405:
1360:
1356:
1319:
1315:
1280:
1276:
1231:
1227:
1180:
1176:
1171:
1167:
1142:10.1038/ncb2347
1136:(10): 1234–43.
1122:
1118:
1087:(17): 1459–68.
1081:Current Biology
1073:
1069:
1024:
1020:
972:
965:
920:
916:
871:
867:
836:(18): 5165–75.
822:
818:
779:
775:
730:
721:
698:10.1038/ncb1066
682:
678:
671:
651:
647:
594:
590:
580:
578:
569:
568:
564:
557:
539:
504:
499:
487:
462:
451:
447:
443:
436:
432:
428:
424:
419:
409:
402:
399:
370:mitotic spindle
362:
306:
289:
280:
235:
223:aurora A kinase
216:
212:
183:mitotic cyclins
140:
130:
24:
17:
12:
11:
5:
2866:
2856:
2855:
2850:
2833:
2832:
2830:
2829:
2824:
2818:
2816:
2809:
2808:
2806:
2805:
2799:
2797:
2790:
2789:
2773:
2772:
2765:
2758:
2750:
2741:
2740:
2738:
2737:
2731:
2729:
2725:
2724:
2722:
2721:
2716:
2711:
2706:
2700:
2698:
2688:
2687:
2672:
2671:
2664:
2657:
2649:
2640:
2639:
2637:
2636:
2631:
2630:
2629:
2624:
2614:
2609:
2604:
2599:
2594:
2589:
2587:CTP synthetase
2584:
2579:
2578:
2577:
2572:
2567:
2562:
2557:
2552:
2542:
2536:
2534:
2527:
2526:
2524:
2523:
2518:
2513:
2507:
2505:
2498:
2497:
2495:
2494:
2493:
2492:
2487:
2482:
2477:
2472:
2467:
2462:
2457:
2452:
2447:
2442:
2437:
2432:
2427:
2422:
2417:
2412:
2407:
2402:
2397:
2392:
2381:
2379:
2372:
2371:
2355:
2354:
2347:
2340:
2332:
2323:
2322:
2319:
2318:
2316:
2315:
2310:
2305:
2301:
2295:
2293:
2289:
2288:
2286:
2285:
2280:
2275:
2269:
2267:
2261:
2260:
2258:
2257:
2252:
2246:
2241:
2236:
2231:
2226:
2216:
2214:
2208:
2207:
2205:
2204:
2199:
2195:
2190:
2185:
2180:
2178:
2169:
2163:
2162:
2160:
2159:
2149:
2144:
2139:
2134:
2129:
2124:
2119:
2113:
2111:
2107:
2106:
2104:
2103:
2098:
2093:
2087:
2085:
2079:
2078:
2076:
2075:
2057:
2030:
2028:
2022:
2021:
2019:
2018:
2013:
2008:
2003:
1998:
1993:
1988:
1983:
1978:
1973:
1968:
1963:
1958:
1953:
1948:
1943:
1937:
1935:
1929:
1928:
1926:
1925:
1911:
1893:
1879:
1864:
1862:
1856:
1855:
1845:
1844:
1837:
1830:
1822:
1816:
1815:
1810:
1798:
1797:External links
1795:
1793:
1792:
1747:
1712:
1677:
1657:10.1038/ncb785
1640:
1602:
1600:
1597:
1594:
1593:
1544:
1495:
1468:Molecular Cell
1454:
1403:
1354:
1313:
1274:
1245:(18): 4321–8.
1225:
1174:
1165:
1116:
1067:
1038:(5): 1555–69.
1018:
963:
934:(8): 1748–64.
914:
865:
816:
773:
719:
692:(12): 1090–4.
676:
669:
645:
588:
577:. 20 July 2014
562:
555:
501:
500:
498:
495:
494:
493:
486:
483:
461:
458:
449:
445:
441:
434:
430:
426:
422:
417:
407:
401:
397:
394:
392:oscillations.
361:
358:
305:
302:
288:
285:
279:
276:
234:
231:
214:
210:
138:
129:
126:
62:, including a
15:
9:
6:
4:
3:
2:
2865:
2854:
2851:
2849:
2846:
2845:
2843:
2828:
2825:
2823:
2820:
2819:
2817:
2814:
2810:
2804:
2801:
2800:
2798:
2795:
2791:
2786:
2782:
2778:
2771:
2766:
2764:
2759:
2757:
2752:
2751:
2748:
2736:
2733:
2732:
2730:
2726:
2720:
2717:
2715:
2712:
2710:
2707:
2705:
2702:
2701:
2699:
2697:
2696:carboxylation
2693:
2689:
2684:
2681:
2677:
2670:
2665:
2663:
2658:
2656:
2651:
2650:
2647:
2635:
2632:
2628:
2625:
2623:
2620:
2619:
2618:
2615:
2613:
2610:
2608:
2605:
2603:
2600:
2598:
2595:
2593:
2590:
2588:
2585:
2583:
2580:
2576:
2573:
2571:
2568:
2566:
2563:
2561:
2558:
2556:
2553:
2551:
2548:
2547:
2546:
2543:
2541:
2538:
2537:
2535:
2532:
2528:
2522:
2519:
2517:
2514:
2512:
2509:
2508:
2506:
2503:
2499:
2491:
2488:
2486:
2483:
2481:
2478:
2476:
2473:
2471:
2468:
2466:
2463:
2461:
2460:Phenylalanine
2458:
2456:
2453:
2451:
2448:
2446:
2443:
2441:
2438:
2436:
2433:
2431:
2428:
2426:
2423:
2421:
2418:
2416:
2413:
2411:
2408:
2406:
2403:
2401:
2398:
2396:
2393:
2391:
2388:
2387:
2386:
2383:
2382:
2380:
2377:
2373:
2368:
2364:
2360:
2353:
2348:
2346:
2341:
2339:
2334:
2333:
2330:
2314:
2311:
2309:
2302:
2300:
2297:
2296:
2294:
2290:
2284:
2281:
2279:
2276:
2274:
2271:
2270:
2268:
2266:
2262:
2256:
2253:
2250:
2247:
2245:
2242:
2240:
2237:
2235:
2232:
2230:
2227:
2225:
2221:
2218:
2217:
2215:
2213:
2209:
2203:
2196:
2194:
2191:
2189:
2182:
2181:
2179:
2177:
2173:
2170:
2164:
2157:
2153:
2150:
2148:
2145:
2143:
2140:
2138:
2135:
2133:
2130:
2128:
2125:
2123:
2120:
2118:
2115:
2114:
2112:
2108:
2102:
2099:
2097:
2094:
2092:
2089:
2088:
2086:
2084:
2080:
2073:
2069:
2065:
2061:
2058:
2055:
2051:
2047:
2043:
2039:
2035:
2032:
2031:
2029:
2027:
2026:CDK inhibitor
2023:
2017:
2014:
2012:
2009:
2007:
2004:
2002:
1999:
1997:
1994:
1992:
1989:
1987:
1984:
1982:
1979:
1977:
1974:
1972:
1969:
1967:
1964:
1962:
1959:
1957:
1954:
1952:
1949:
1947:
1944:
1942:
1939:
1938:
1936:
1934:
1930:
1923:
1919:
1915:
1912:
1909:
1905:
1901:
1897:
1894:
1891:
1887:
1883:
1880:
1877:
1873:
1869:
1866:
1865:
1863:
1861:
1857:
1853:
1850:
1843:
1838:
1836:
1831:
1829:
1824:
1823:
1820:
1814:
1811:
1808:
1804:
1801:
1800:
1789:
1785:
1780:
1775:
1770:
1765:
1761:
1757:
1753:
1748:
1744:
1740:
1735:
1730:
1726:
1722:
1718:
1713:
1709:
1705:
1700:
1695:
1691:
1687:
1683:
1678:
1674:
1670:
1666:
1662:
1658:
1654:
1651:(5): 358–66.
1650:
1646:
1641:
1637:
1633:
1629:
1625:
1621:
1617:
1613:
1609:
1604:
1603:
1589:
1585:
1580:
1575:
1571:
1567:
1563:
1559:
1555:
1548:
1540:
1536:
1532:
1528:
1523:
1518:
1515:(5): 645–55.
1514:
1510:
1506:
1499:
1491:
1487:
1482:
1477:
1474:(5): 543–53.
1473:
1469:
1465:
1458:
1450:
1446:
1442:
1438:
1434:
1430:
1426:
1422:
1418:
1414:
1407:
1399:
1395:
1390:
1385:
1381:
1377:
1374:(3): 381–95.
1373:
1369:
1365:
1358:
1350:
1346:
1341:
1336:
1332:
1328:
1324:
1317:
1309:
1305:
1301:
1297:
1293:
1289:
1285:
1278:
1270:
1266:
1261:
1256:
1252:
1248:
1244:
1240:
1236:
1229:
1221:
1217:
1212:
1207:
1202:
1197:
1193:
1189:
1185:
1178:
1169:
1161:
1157:
1152:
1147:
1143:
1139:
1135:
1131:
1127:
1120:
1112:
1108:
1104:
1100:
1095:
1090:
1086:
1082:
1078:
1071:
1063:
1059:
1054:
1049:
1045:
1041:
1037:
1033:
1029:
1022:
1014:
1010:
1005:
1000:
996:
992:
989:(4): 786–96.
988:
984:
980:
976:
970:
968:
959:
955:
950:
945:
941:
937:
933:
929:
925:
918:
910:
906:
901:
896:
892:
888:
884:
880:
876:
869:
861:
857:
852:
847:
843:
839:
835:
831:
827:
820:
812:
808:
804:
800:
796:
792:
789:(3): 314–25.
788:
784:
777:
769:
765:
760:
755:
751:
747:
743:
739:
735:
728:
726:
724:
715:
711:
707:
703:
699:
695:
691:
687:
680:
672:
670:0-8153-3218-1
666:
662:
661:
656:
649:
641:
637:
632:
627:
623:
619:
615:
611:
607:
603:
599:
592:
576:
572:
566:
558:
552:
548:
544:
537:
535:
533:
531:
529:
527:
525:
523:
521:
519:
517:
515:
513:
511:
509:
507:
502:
492:
489:
488:
482:
478:
476:
472:
466:
457:
455:
438:
413:
411:
393:
390:
385:
382:
378:
373:
371:
367:
357:
353:
349:
346:
342:
337:
335:
331:
327:
323:
319:
315:
311:
301:
297:
295:
284:
275:
271:
267:
263:
261:
257:
252:
249:
245:
239:
230:
226:
224:
220:
207:
203:
198:
196:
192:
188:
184:
180:
176:
172:
168:
164:
160:
156:
152:
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2569:
2234:Prometaphase
1759:
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227:
199:
157:and S and M
144:
115:
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43:
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34:
2255:Cytokinesis
2224:Preprophase
2168:checkpoints
975:Passmore LA
475:BTRC (gene)
345:WD40 repeat
324:, and N is
195:cytokinesis
99:proteolysis
46:) is an E3
2842:Categories
2803:DNA ligase
2694:dependent
2480:Tryptophan
2455:Methionine
2440:Isoleucine
2400:Asparagine
2176:Interphase
2166:Phases and
1849:Cell cycle
1719:. review.
1684:. review.
497:References
400:transition
326:asparagine
314:amino acid
278:CDC27/APC3
171:chromatids
103:proteasome
97:-mediated
56:proteasome
52:cell cycle
2475:Threonine
2435:Histidine
2425:Glutamine
2420:Glutamate
2405:Aspartate
2299:Apoptosis
2249:Telophase
2239:Metaphase
2034:INK4a/ARF
440:Once in G
334:glutamate
332:and E is
175:metaphase
147:metaphase
118:nanometre
95:ubiquitin
84:conserved
40:cyclosome
2853:Proteins
2787:6.5-6.6)
2485:Tyrosine
2410:Cysteine
2395:Arginine
2369:6.1-6.3)
2244:Anaphase
2229:Prophase
1852:proteins
1788:21087491
1743:12208841
1708:10465783
1673:25403043
1665:11988738
1588:15469984
1539:16366514
1531:11389834
1490:15916961
1449:25369228
1368:Genetics
1349:12953067
1308:12082146
1220:21209074
1160:21926987
1103:12956947
1062:10793135
1013:12574115
958:25490258
909:19668213
860:11566880
811:29467714
803:15678131
783:Oncogene
768:22084387
714:30582585
706:14634663
640:25043029
485:See also
381:cyclin B
377:Cyclin A
318:arginine
233:Subunits
163:separase
151:anaphase
128:Function
60:proteins
31:binding.
2848:Mitosis
2781:ligases
2777:Enzymes
2676:Ligases
2465:Proline
2445:Leucine
2430:Glycine
2390:Alanine
2363:ligases
2359:Enzymes
2313:Meiosis
2220:Mitosis
2212:M phase
2193:S phase
2060:cip/kip
1779:3095333
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1636:9334304
1616:Bibcode
1608:Science
1441:8939846
1421:Bibcode
1413:Science
1398:3894160
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1269:7925276
1211:3060455
1151:3188299
1111:5942532
949:4444369
900:2759704
759:3203452
631:4456660
610:Bibcode
581:22 July
322:Leucine
191:mitosis
167:cohesin
159:cyclins
155:securin
2692:Biotin
2550:Cullin
2490:Valine
2470:Serine
2450:Lysine
2152:Cullin
2038:p14arf
1860:Cyclin
1809:(MeSH)
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396:M to G
341:et al.
330:lysine
244:cullin
122:cancer
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64:cullin
2728:Other
2560:UBE3A
2308:phase
2202:phase
2188:phase
2127:Cdc42
2122:Cdc25
2110:Other
1892:, B3)
1669:S2CID
1535:S2CID
1445:S2CID
1107:S2CID
1053:14867
807:S2CID
710:S2CID
410:phase
260:Cdc23
256:Cdc27
213:and G
202:Cdc20
179:poles
76:Apc11
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2575:UBR1
2565:Mdm2
2156:CUL7
2117:Cdc2
1784:PMID
1739:PMID
1704:PMID
1661:PMID
1632:PMID
1584:PMID
1527:PMID
1509:Cell
1486:PMID
1437:PMID
1394:PMID
1345:PMID
1304:PMID
1265:PMID
1216:PMID
1156:PMID
1099:PMID
1058:PMID
1009:PMID
954:PMID
905:PMID
856:PMID
799:PMID
764:PMID
702:PMID
665:ISBN
636:PMID
583:2014
551:ISBN
206:Cdh1
204:and
193:and
72:RING
68:Apc2
2813:6.6
2794:6.5
2683:6.4
2531:6.3
2502:6.2
2376:6.1
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2137:E2F
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