BIOLOGICAL OVERVIEW

Rca1 specifically inhibits Cdh1^Fzr-dependent anaphase-promoting complex/cyclosome (APC) activity and prevents cyclin degredation in G2. The APC is a multisubunit ubiquitin ligase that targets several mitotic regulators for degradation and thereby triggers an exit from mitosis. APC activity is restricted to mitotic stages and G1. This is achieved by the cell cycle-dependent association of proteins encoded by fizzy (fzy) and fizzy-related (fzr) genes, respectively, termed here Cdc20Fzy and Cdh1Fzr, referring to their homologs Cdc20 and Cdh1, found in yeast. In the absence of rca1 function, mitotic cyclins are prematurely degraded, and cells fail to enter mitosis. This phenotype is reminiscent of the phenotype produced by overexpression of Cdh1^Fzr. Double-mutant analysis demonstrates that premature cyclin destruction in rca1 mutants is mediated by Cdh1^Fzr. Furthermore, Rca1 can block the effects of Cdh1^Fzr overexpression, supporting the notion that Rca1 inhibits Cdh1^Fzr-dependent APC activity. Coimmunoprecipitation experiments reveal that Rca1 and Cdh1^Fzr are in a complex that also contains the APC component Cdc27. Collectively, these data show that Rca1 is a negative regulator of Cdh1^Fzr-dependent APC activity. It is suggested that a similar function is required in all cells in which kinase activity is low during G2 to prevent a premature activation of the APC by Cdh1 (Grosskortenhaus, 2002).

Binding of Cdc20 and Cdh1 to the APC is differentially regulated. APC-Cdc20 activity is present during mitosis and initiates the metaphase-anaphase transition. The association of Cdc20 with the APC requires phosphorylation of at least one subunit of the APC. Several mitotic kinases have been implicated in this phosphorylation. The dependency of APC phosphorylation on Cdc20 binding ensures that APC-Cdc20 is only active during mitosis. During prophase and prometaphase, APC-Cdc20 activity is furthermore restrained by the spindle checkpoint. This system monitors the presence of unattached kinetochores. Until kinetochores are bound by spindles, they serve as an assembly point for active Mad2 protein. Mad2 binds to Cdc20 and inhibits APC activity. Once all kinetochores are attached and chromosomes are aligned on the metaphase plate, Mad2 inhibition of APC-Cdc20 activity is released (Grosskortenhaus, 2002 and references therein).

Cdh1 is found in association with the APC during later stages of mitosis and G1. This interaction depends on the phosphorylation status of Cdh1 (Kramer, 2000; Zachariae, 1998). Only unphosphorylated Cdh1 is able to bind to and activate the APC (Kotani, 1999; Kramer, 2000). Cdk1 and Cdk2 mediate Cdh1 phosphorylation. Thus, only during stages of low Cdk kinase activity will Cdh1 activate the APC. These requirements are fulfilled during later stages of mitosis, when APC-Cdc20 has induced the degradation of mitotic cyclins, and during G1, when Cdk kinase activity is low. However, the G2 stage is also characterized by low Cdk kinase activity. How Cdh1-dependent APC activity is prevented in these situations has not been addressed so far (Grosskortenhaus, 2002 and references therein).

The mitotic cyclins in Drosophila (Cyclin A [CycA], Cyclin B [CycB], and Cyclin B3) are stable in interphase, degraded during mitosis, and continue to be unstable throughout G1. Cdc20^Fzy is required for mitotic cyclin destruction at the metaphase-anaphase transition and is thought to mediate the bulk of cyclin degradation in the first 16 cell cycles in Drosophila. Mutants in fzy arrest in metaphase of cell cycle 16 when the maternal supply of Cdc20^Fzy is exhausted. Overexpression of fzy does not cause abnormal cyclin destruction. Thus, Cdc20^Fzy is not able to activate the APC at other cell cycle stages. This likely reflects the inability of Cdc20 to interact with unphosphorylated APC (Grosskortenhaus, 2002 and references therein).

Mitotic cyclins remain unstable during G1, mediated by APC-Cdh1^Fzr-dependent degradation (Sigrist, 1997). The first G1 phase during embryogenesis is not established in fzr mutants, and cells perform an additional S phase, presumably triggered by the S phase activity of the CycA/Cdk1 complex (Sigrist, 1997; Sprenger, 1997). Cdh1^Fzr mRNA expression cannot be detected during the cellular blastoderm stages, but low levels of Cdh1^Fzr are presumably present. High levels of Cdh1^Fzr are expressed during stage 11 of embryogenesis, when most cells are in the 16^th cell cycle, shortly before they enter the first G1 phase. In contrast to Cdc20^Fzy, APC activation by Cdh1^Fzr can be induced ectopically by its overexpression (Sigrist, 1997). During embryogenesis, this results in degradation of mitotic cyclins in G2 of cell cycle 16 and a failure to execute mitosis 16 (Grosskortenhaus, 2002 and references therein).

Rca1 is an essential inhibitor of the anaphase-promoting complex/cyclosome (APC) in Drosophila. APC activity is restricted to mitotic stages and G1 by its activators Cdc20-Fizzy (Cdc20^Fzy) and Cdh1-Fizzy-related (Cdh1^Fzr), respectively. In rca1 mutants, cyclins are degraded prematurely in G2 by APC-Cdh1^Fzr-dependent proteolysis, and cells fail to execute mitosis. Overexpression of Cdh1^Fzr mimics the rca1 phenotype, and coexpression of Rca1 blocks this Cdh1^Fzr function. Previous studies have shown that phosphorylation of Cdh1 prevents its interaction with the APC. The data reveal another mode of APC regulation; this one is fulfilled by Rca1 at the G2 stage, when low Cdk activity is unable to inhibit Cdh1^Fzr interaction (Grosskortenhaus, 2002).

In rca1 mutants, levels of mitotic cyclins are reduced during interphase of the 16^th cell cycle. This finding is in contrast to a previous study in which no differences in CycA levels were found (Dong, 1997). However, this premature cyclin disappearance becomes obvious only when mutant and rescued segments in a given embryo are compared and is more difficult to detect when mutant and wt embryos are compared. The lower levels of mitotic cyclins are not caused by changes in cyclin transcription or translation, since mitotic cyclins accumulate normally at the beginning of cell cycle 16. Mitotic cyclins are usually stable in interphase cells of cellularized Drosophila embryos. It is therefore concluded that their disappearance in rca1 mutants is caused by premature degradation. The remaining cyclin levels are apparently not sufficient to allow entry into mitosis. In Drosophila, CycA and CycB are cytoplasmic during interphase and accumulate in the nucleus only during prophase. It has been speculated that the nuclear accumulation of mitotic cyclins is required for certain mitotic events like DNA condensation. Rca1 is a nuclear protein and could be required to prevent degradation of mitotic cyclins, specifically in the nucleus. Another possibility is that Rca1 sequesters parts of the degradation machinery in the nucleus away from the bulk of mitotic cyclins present in the cytoplasm (Grosskortenhaus, 2002).

In rca1 mutant embryos, residual levels of cytoplasmic CycA and CycB are visible. Supplying additional CycA (but not CycB) is sufficient to rescue the mitotic failure of rca1 mutants. This demonstrates that CycA is the crucial mitotic factor missing in rca1 mutant embryos (Grosskortenhaus, 2002).

The requirements for rca1 function are not restricted to embryogenesis. Clonal analysis of rca1 function shows that imaginal cells lacking rca1 also have reduced cyclin levels and fail to proliferate normally. In these cells, large nuclei are found typical for cells undergoing endocycles. An overreplication has been reported in imaginal discs lacking Cdk1 activity. Since mitotic cyclins are degraded in rca1 mutant cells, it is expected that low Cdk1 kinase activity could result in the lack of proliferation and in overreplication of the genome. A detailed analysis of the DNA content and DNA replication pattern will reveal whether rca1 mutant cells similarly undergo endocycles (Grosskortenhaus, 2002).

The APC targets cyclins for degradation, and its activity is normally restricted to mitotic stages and G1. However, in rca1 mutants, premature cyclin destruction during G2 is observed, indicating that Rca1 is required to inhibit the APC and thus ensures high mitotic cyclin levels for mitotic entry (Grosskortenhaus, 2002).

On a molecular level, Rca1 could inhibit APC ubiquitin ligase activity directly, or it might specifically prevent activation of the APC by Cdc20^Fzy and Cdh1^Fzr. Several lines of evidence suggest that Rca1 is a specific inhibitor of Cdh1^Fzr-dependent APC activity and does not affect APC-Cdc20^Fzy. First of all, premature degradation of cyclins in rca1 mutants depends on fzr gene function. Embryos mutant for fzr and rca1 do not degrade cyclins prematurely, and mitosis 16 is restored. Thus, fzr is epistatic to rca1. In contrast, rca1 is epistatic to fzy (P. O'Farrell, personal communication to Grosskortenhaus, 2002). In addition, overexpression studies also support the specificity of Rca1. Overexpression of Cdc20^Fzy is without consequences for cyclin levels and cell cycle progression (Sigrist, 1997). In contrast, overexpression of Cdh1^Fzr resulted in premature cyclin degradation, as in rca1 mutants. The coexpression of Rca1 negates this phenotype, indicating that Cdh1^Fzr and Rca1 oppose each other (Grosskortenhaus, 2002).

During the first 16 cell cycles in Drosophila, Cdc20^Fzy is thought to be the major APC-activating protein, since Cdh1^Fzr is present at higher levels only at later stages. Uniform overexpression of HA-Rca1 has no influence on cell cycle progression or cyclin degradation during the first 16 divisions, indicating that Rca1 does not inhibit Cdc20^Fzy-dependent APC activity (Grosskortenhaus, 2002).

Ubiquitous overexpression of HA-Rca1 also has no influence on the establishment of the G1 state. This is in contrast to fzr mutants that fail to downregulate mitotic cyclins levels after mitosis 16 and that do not establish a G1 phase. However, HA-Rca1 itself is degraded in G1 cells and thus cannot influence Cdh1^Fzr function. It is also suggested that Rca1 activity is subjected to cell cycle-specific regulation and it is expected that Rca1 function is downregulated during mitosis to allow Cdh1^Fzr activity during later stages of mitosis and at the beginning of G1 (Grosskortenhaus, 2002).

A biochemical interaction between Rca1 and Cdh1^Fzr was seen in coimmunoprecipitation experiments. Using embryonic extracts, it was shown that both proteins are present in a complex. The complex precipitated from embryonic extracts also contains the APC component Cdc27. Thus, Rca1 might be able to inhibit preformed APC-Cdh1^Fzr complexes. Additionally it could prevent a fruitful association of Cdh1^Fzr with the APC. Regardless of the exact biochemical composition of the Rca1-containing complex, all of the data support the conclusion that Rca1 is a specific inhibitor of Cdh1^Fzr-dependent APC activity. This function of Rca1 is necessary during the G2 stage of the cell cycle to prevent a premature activation of the APC-Cdh1^Fzr complex (Grosskortenhaus, 2002).

Cdh1 is also regulated by phosphorylation. Only unphosphorylated Cdh1 can bind to and activate the APC, and several kinases have been implicated in the phosphorylation of Cdh1, including Cdk1 and Cdk2. Accordingly, no Cdh1-dependent APC activity was found during S phase and early mitotic stages. When degradation of mitotic cyclins abate Cdk1 activity after the metaphase-anaphase transition, unphosphorylated Cdh1 is thought to activate the APC. This activity is then maintained during the G1 state and turned off when cells start to accumulate Cdk2 activity at the G1-S transition. The G2 state is also characterized by low Cdk kinase activity, yet not in all cell cycles. In Drosophila, Cdk1 is inhibited during G2 stages by tyrosine phosphorylation. But during the first 15 divisions, Cdk kinase activity is provided by CycE/Cdk2 activity that is present throughout the cell cycle, including G2. During cell cycle 16, CycE/Cdk2 kinase activity drops, since CycE mRNA is downregulated and the CycE/Cdk2 inhibitor Dacapo is upregulated. Thus, in G2 of cell cycle 16, Cdk1 as well as Cdk2 activity is expected to be low. At this stage, phosphorylation of Cdh1^Fzr cannot prevent its association with the APC, and the requirements for Rca1 become evident. Accordingly, Rca1 is dispensable when CycE is overexpressed during cell cycle 16. Thus, phosphorylation and interaction with Rca1 can control Cdh1^Fzr activity during G2. However, Rca1- and CycE-dependent phosphorylation of the APC are not completely redundant. In CycA mutant embryos, maternally provided CycA is normally sufficient to allow execution of mitosis 15, despite low CycA levels. In rca1;CycA double mutants, cells arrest before mitosis 15, likely caused by a further reduction in CycA. During this stage, CycE is still present but apparently cannot substitute completely for the lack of rca1 function (Grosskortenhaus, 2002).

It is expected that Cdh1 inhibition by an Rca1-like function is also required in other organisms. In human cells, Cdh1 phosphorylation is also low when most cells are in late S phase and G2, but only low APC activity is detected. Thus, human cells must also have a mechanism preventing APC-Cdh1 activation when Cdh1 phosphorylation is low (Grosskortenhaus, 2002).

Recently, potential homologs of Rca1 have been identified in Xenopus, mouse, and humans and named Emi1 (Reimann, 2001). Emi1 from Xenopus inhibits Cdc20 activity in the Xenopus system. In contrast, Rca1 specifically inhibits APC-Cdh1^Fzr, but not APC-Cdc20^Fzy activity. Databank searches reveal that the Drosophila genome does not contain an additional protein that resembles Emi1 or Rca1. It is thus believed that Rca1 has specificity different from that of Emi1. This difference might reflect the manner in which cell cycle progression is controlled in these organisms. In Drosophila, CycA- and CycB-containing Cdk1 complexes are targets for inhibitory phosphorylation. In contrast, the CycA/Cdk1 complex in Xenopus is not subject to this modification, and one can expect Cdk1 activity even in G2. That could result in the phosphorylation of the APC and activation by Cdc20, even before the spindle checkpoint is activated. Thus, Emi1 might have been adapted to these specific requirements in Xenopus to suppress Cdc20-dependent APC function before mitosis. Rca1, in contrast, is required to prevent APC-Cdh1^Fzr activity when Cdk1 kinase activity is low in G2, an environment that is permissive for APC-Cdh1 complex formation. Significantly, recent work on the human form of Emi1 has revealed that this protein inhibits the APC-Cdh1 complex (P. Jackson, personal communication to Grosskortenhaus, 2002). In S. pombe, which is also characterized by low Cdk kinase activity in G2, premature APC-Ste9 (the Cdh1 homolog) activity is probably prevented by very low Ste9 protein levels during G2. Thus, different ways of preventing premature APC activation at the G2 stage have been selected in various organisms and by different cell types within an organism. These data reveal the importance of APC downregulation by the Rca1 protein that is specific for the APC-Cdh1^Fzr activity. In addition to the Emi1/Rca1 class of proteins, inhibition of the APC-Cdh1 complex is also mediated by a protein related to Mad2 protein. The biological role of this inhibition has not been elucidated so far (Grosskortenhaus, 2002).

Thus, a number of different mechanisms regulating the activity of the APC-Cdh1 have been identified recently. It has been shown that APC activity is restricted to mitotic stages and G1. The data on Rca1 demonstrate a novel control of APC-Cdh1 activity that is necessary to prevent unwanted APC activity at the G2 stage. It is expected that this mechanism of controlling APC-Cdh1 activity is also involved in the downregulation of APC-Cdh1 activity at the G1-S transition (Grosskortenhaus, 2002).

Spatiotemporal control of mitotic exit during anaphase by an aurora B-Cdk1 crosstalk

According to the prevailing 'clock' model, chromosome decondensation and nuclear envelope reformation when cells exit mitosis are byproducts of Cdk1 inactivation at the metaphase-anaphase transition, controlled by the spindle assembly checkpoint. However, mitotic exit was recently shown to be a function of chromosome separation during anaphase, assisted by a midzone Aurora B phosphorylation gradient - the 'ruler' model. This study found that Cdk1 remains active during anaphase due to ongoing APC/C(Cdc20)- and APC/C(Cdh1)-mediated degradation of B-type Cyclins in Drosophila and human cells. Failure to degrade B-type Cyclins during anaphase prevented mitotic exit in a Cdk1-dependent manner. Cyclin B1-Cdk1 localized at the spindle midzone in an Aurora B-dependent manner, with incompletely separated chromosomes showing the highest Cdk1 activity. Slowing down anaphase chromosome motion delayed Cyclin B1 degradation and mitotic exit in an Aurora B-dependent manner. Thus, a crosstalk between molecular 'rulers' and 'clocks' licenses mitotic exit only after proper chromosome separation (Afonso, 2019).

Taken together, this work reveals that degradation of B-type Cyclins specifically during anaphase is rate-limiting for mitotic exit among animals that diverged more than 900 million years ago. Most importantly, Cdk1 activity during anaphase was shown to be a function of chromosome separation and is spatially regulated by Aurora B localization and activity at the spindle midzone. In concert with previous work, the findings unveil an unexpected crosstalk between molecular 'rulers' (Aurora B) and 'clocks' (B-type Cyclins-Cdk1) that ensures that cells only exit mitosis after proper chromosome separation during anaphase, consistent with the previously proposed chromosome separation checkpoint hypothesis. An Aurora B-dependent spatial control mechanism regulating normal NER in human cells has been recently confirmed. However, nuclear envelope defects associated with incomplete chromosome separation during anaphase (namely, anaphase lagging chromosomes due to mitotic errors) were proposed as an inevitable pathological condition. The present work provides yet additional evidence for a molecular network operating during anaphase that promotes chromosome segregation fidelity by controlling mitotic exit in space and time. According to this model, APC/CCdc20 mediates the initial degradation of Cyclin B1 during metaphase under SAC control. The consequent decrease in Cdk1 activity as cells enter anaphase targets Aurora B to the spindle midzone (via Subito/Mklp2/kinesin-6); Aurora B at the spindle midzone (counteracted by PP1/PP2A phosphatases on chromatin establishes a phosphorylation gradient that locally delays APC/CCdc20- and APC/CCdh1-mediated degradation of residual Cyclin B1 (and possibly B3) at the spindle midzone, at least in Drosophila cells. Localization experiments in human cells suggest that Cdk1 itself might be enriched at the spindle midzone. Consequently, as chromosomes separate and move away from the spindle midzone, Cdk1 activity decreases, allowing the PP1/PP2A-mediated dephosphorylation of Cdk1 and Aurora B substrates (e.g., Lamin B and Condensin I) necessary for mitotic exit. This model is consistent with the recent demonstration that Cdk1 inactivation promotes the recruitment of PP1 phosphatase to chromosomes to locally oppose Aurora B phosphorylation and recent findings in budding yeast demonstrating equivalent phosphorylation and dephosphorylation events during mitotic exit. It is also consistent with a premature Greatwall inactivation and PP2A:B55 reactivation that would be predicted after acute Cdk1 inactivation during anaphase. Most important, this model provides an explanation for the coordinated action of two unrelated protein kinases that likely regulate multiple substrates required for mitotic exit (Afonso, 2019).

Previous landmark work has carefully monitored the kinetics of Cyclin B1 degradation in living human HeLa and rat kangaroo Ptk1 cells during mitosis, and concluded that Cyclin B1 was degraded by the end of metaphase, becoming essentially undetectable as cells entered anaphase. However, it was noticed that, consistent with the current findings, a small pool of Cyclin B1 continued to be degraded during anaphase in Ptk1 cells. Subsequent work investigating cellular response to anti-mitotic drugs has also shown that human DLD-1 cells undergoing normal mitosis entered anaphase with as much as 32% of Cyclin B1 compared to metaphase levels, suggesting that human cells enter anaphase with significant Cdk1 activity. Indeed, quantitative analysis with a FRET biosensor in human HeLa cells also revealed residual Cdk1 activity during anaphase. However, the significance of persistent Cdk1 activity for the control of anaphase duration and mitotic exit was not investigated in these original studies. Previous works also clearly demonstrated that forcing Cdk1 activity during anaphase through expression of non-degradable Cyclin B1 (and Cyclin B3 in Drosophila) prevents chromosome decondensation and NER. However, while these works suggested the existence of different Cyclin B1 thresholds that regulate distinct mitotic transitions, expression of non-degradable Cyclin B1 could be interpreted as an artificial gain of function that preserves Cdk1 activity during anaphase. For example, it was shown that expression of non-degradable Cyclin B1 during anaphase 'reactivates' the SAC, inhibiting APC/CCdc20. The current work demonstrates in five different experimental systems, from flies to humans, including primary tissues, that Cdk1 activity persists during anaphase and is rate-limiting for the control of mitotic exit. Failure to degrade B-type Cyclins during anaphase blocked cells in an anaphase-like state with separated sister chromatids that remained condensed for several hours, whereas complete Cdk1 inactivation in anaphase triggered chromosome decondensation and NER. Importantly, if a positive feedback loop imposed by phosphatases was sufficient to drive mitotic exit simply by reverting the effect of Cdk1 phosphorylation prior to anaphase, cells would exit mitosis regardless of the remaining pool of B-type Cyclins that sustains Cdk1 activity during anaphase. The main conceptual implication of these findings is that, contrary to what was previously assumed, mitotic exit is determined during anaphase and not at the metaphase-anaphase transition under SAC control (Afonso, 2019).

This model also implies that persistent Cyclin B1-Cdk1 in anaphase is spatially regulated by a midzone Aurora B gradient. Indeed, a residual pool of Cyclin B1-Cdk1 was identified enriched at the spindle midzone and midbody, this localization was dependent on Aurora B activity and localization at the spindle midzone. Interestingly, human Cyclin B2 (which contains a recognizable KEN box), as well as Cdk1, were identified at the midbody and Cdk1 inactivation during late mitosis was required for the timely completion of cytokinesis in human cells. Thus, it is possible that in human cells, Cdk1 activity during anaphase is regulated not only by Cyclin B1, but also by Cyclin B2. Importantly, this model predicted the existence of a midzone-centered Cdk1 activity gradient during anaphase, which was confirmed experimentally by targeting a FRET reporter of Cdk1 activity to chromosomes (Afonso, 2019).

Finally, the experiments indicate that Aurora B activity regulates Cyclin B1 homeostasis and consequently anaphase duration in the presence of incompletely separated chromosomes. One possibility is that direct Cyclin B1 phosphorylation by Aurora B spatially regulates Cyclin B1 degradation during anaphase, mediated by both APC/CCdc20 and APC/CCdh1. Another non-mutually exclusive possibility is that Aurora B indirectly controls Cyclin B1 during anaphase by regulating APC/CCdc20 and/or APC/CCdh1 activity, as recently shown for Cdk1. Future work will be necessary to test these hypotheses (Afonso, 2019).

In conclusion, this study has uncovered an unexpected level of regulation at the end of mitosis in metazoans and reconciled what were thought to be antagonistic models of mitotic exit relying either on molecular 'clocks' or on 'rulers'. These findings have profound implications to fundamental understanding of how tissue homeostasis is regulated, perturbation of which is a hallmark of human cancers (Afonso, 2019).

GENE STRUCTURE

cDNA clone length - 1577

Bases in 5' UTR - 98

Exons - 1

Bases in 3' UTR - 220

PROTEIN STRUCTURE

Amino Acids - 412

Structural Domains

Regulator of cyclin A encodes a novel protein (Dong, 1997)

EVOLUTIONARY HOMOLOGS

EMI1 switches from being a substrate to an inhibitor of APC/C(CDH1) to start the cell cycle

Mammalian cells integrate mitogen and stress signalling before the end of G1 phase to determine whether or not they enter the cell cycle. Before cells can replicate their DNA in S phase, they have to activate cyclin-dependent kinases (CDKs), induce an E2F transcription program and inactivate the anaphase-promoting complex (APC/C(CDH1), also known as the cyclosome), which is an E3 ubiquitin ligase that contains the co-activator CDH1 (also known as FZR, encoded by FZR1; see Drosophila Fizzy related). It was recently shown that stress can return cells to quiescence after CDK2 activation and E2F induction but not after inactivation of APC/C(CDH1), which suggests that APC/C(CDH1) inactivation is the point of no return for cell-cycle entry. Rapid inactivation of APC/C(CDH1) requires early mitotic inhibitor 1 (EMI1; see Drosophila Regulator of cyclin A1), but the molecular mechanism that controls this cell-cycle commitment step is unknown. This study shows using human cell models that cell-cycle commitment is mediated by an EMI1-APC/C(CDH1) dual-negative feedback switch, in which EMI1 is both a substrate and an inhibitor of APC/C(CDH1). The inactivation switch triggers a transition between a state with low EMI1 levels and high APC/C(CDH1) activity during G1 and a state with high EMI1 levels and low APC/C(CDH1) activity during S and G2. Cell-based analysis, in vitro reconstitution and modelling data show that the underlying dual-negative feedback is bistable and represents a robust irreversible switch. This study suggests that mammalian cells commit to the cell cycle by increasing CDK2 activity and EMI1 mRNA expression to trigger a one-way APC/C(CDH1) inactivation switch that is mediated by EMI1 transitioning from acting as a substrate of APC/C(CDH1) to being an inhibitor of APC/C(CDH1) (Cappell, 2018).

date revised: 3 January 2020

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