Mitotic exit in two dimensions

Molecular Network Dynamics Group of Hungarian Academy of Sciences and Budapest University of Technology and Economics, 1111 Budapest Gellert ter 4, Hungary.
Journal of Theoretical Biology (Impact Factor: 2.12). 11/2007; 248(3):560-73. DOI: 10.1016/j.jtbi.2007.06.014
Source: PubMed


Metaphase of mitosis is brought about in all eukaryotes by activation of cylin-dependent kinase (Cdk1), whereas exit from mitosis requires down-regulation of Cdk1 activity and dephosphorylation of its target proteins. In budding yeast, the completion of mitotic exit requires the release and activation of the Cdc14 protein-phosphatase, which is kept inactive in the nucleolus during most of the cell cycle. Activation of Cdc14 is controlled by two regulatory networks called FEAR (Cdc fourteen early anaphase release) and MEN (mitotic exit network). We have shown recently that the anaphase promoting protease (separase) is essential for Cdc14 activation, thereby it makes mitotic exit dependent on execution of anaphase. Based on this finding, we have proposed a new model for mitotic exit in budding yeast. Here we explain the essence of the model by phaseplane analysis, which reveals two underlying bistable switches in the regulatory network. One bistable switch is caused by mutual activation (positive feedback) between Cdc14 activating MEN and Cdc14 itself. The mitosis-inducing Cdk1 activity inhibits the activation of this positive feedback loop and thereby controlling this switch. The other irreversible switch is generated by a double-negative feedback (mutual antagonism) between mitosis inducing Cdk1 activity and its degradation machinery (APC(Cdh1)). The Cdc14 phosphatase helps turning this switch in favor of APC(Cdh1) side. Both of these bistable switches have characteristic thresholds, the first one for Cdk1 activity, while the second for Cdc14 activity. We show that the physiological behaviors of certain cell cycle mutants are suggestive for those Cdk1 and Cdc14 thresholds. The two bistable switches turn on in a well-defined order. In this paper, we explain how the activation of Cdc20 (which causes the activation of separase and a decrease of Cdk1 kinase activity) provides an initial trigger for the activation of the MEN-Cdc14 positive feedback loops, which in turn, flips the second irreversible Cdk-APC(Cdh1) switch on the APC(Cdh1) side).

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    • "MEN Overview: Consistent with its nonessential nature, FEARdriven Cdc14 release cannot drive full exit from mitosis: it is incomplete and results in very little accumulation of the phosphatase in the cytoplasm. Complete mitotic exit requires the MEN, which promotes robust relocalization of Cdc14, leading to full dephosphorylation of cytoplasmic CDK substrates and numerous downstream events (Charles et al. 1998; Bosl and Li 2005; Toth et al. 2007). The core MEN pathway consists of three functional modules: the G protein Tem1, the protein kinase Cdc15, and the protein kinases Dbf2 and Dbf20 in complex with their co-activating protein Mob1 (Figure 10) (Visintin et al. 1998; Shou et al. 1999; Tinker-Kulberg and Morgan 1999; Bardin et al. 2000; Jaspersen and Morgan 2000; Pereira and Schiebel 2001; Visintin and Amon 2001). "
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    ABSTRACT: Productive cell proliferation involves efficient and accurate splitting of the dividing cell into two separate entities. This orderly process reflects coordination of diverse cytological events by regulatory systems that drive the cell from mitosis into G1. In the budding yeast Saccharomyces cerevisiae, separation of mother and daughter cells involves coordinated actomyosin ring contraction and septum synthesis, followed by septum destruction. These events occur in precise and rapid sequence once chromosomes are segregated and are linked with spindle organization and mitotic progress by intricate cell cycle control machinery. Additionally, critical paarts of the mother/daughter separation process are asymmetric, reflecting a form of fate specification that occurs in every cell division. This chapter describes central events of budding yeast cell separation, as well as the control pathways that integrate them and link them with the cell cycle.
    Genetics 12/2012; 192(4):1165-202. DOI:10.1534/genetics.112.145516 · 5.96 Impact Factor
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    • "Various mathematical models that attempt to quantify the molecular mechanisms in cell cycle for different organisms have been reported in literature including those for Saccharomyces cerevisiae, Schizosaccharomyces pombe , Xenopus Egg, Caulobacter crescentus and Mammalian system (Goldbeter 1991; Norel and Agur 1991; Aguda and Tang 1999; Aguda 1999; Gardner et al. 1998; Hatzimanikatis et al. 1999; Obeyesekere et al. 1999; Qu et al. 2003; Srividhya and Gopinathan 2006; Chauhan et al. 2008; Davidich and Bornholdt 2008; Faure et al. 2009; Iwamoto et al. 2011; Vasireddy and Biswas 2004). Pioneering works of Novak and Tyson's research group have established a strong foundation to mathematically model and analyze the cell cycle regulation of diverse model organisms (Tyson 1991; Novak and Tyson 1993, 1995, 1997; Marlovits et al. 1998; Novak et al. 1999, 2001; Ciliberto and Tyson 2000; Sveiczer et al. 2000; Chen et al. 2000, 2004; Tyson and Novak 2001, 2011; Ciliberto et al. 2003, 2005; Lovrics et al. 2006; Csikasz-Nagy et al. 2006, 2007; Toth et al. 2007; Li et al. 2009; Zwolak et al. 2009; Barik et al. 2010; Ball et al. 2011; Vinod et al. 2011). Their models have also successfully simulated several mutants, uncovered several governing principles and predicted several testable hypothesis, thus providing insights into the regulatory mechanisms. "
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    ABSTRACT: Unlabelled: Cell cycle is the central process that regulates growth and division in all eukaryotes. Based on the environmental condition sensed, the cell lies in a resting phase G0 or proceeds through the cyclic cell division process (G1→S→G2→M). These series of events and phase transitions are governed mainly by the highly conserved Cyclin dependent kinases (Cdks) and its positive and negative regulators. The cell cycle regulation of fission yeast Schizosaccharomyces pombe is modeled in this study. The study exploits a detailed molecular interaction map compiled based on the published model and experimental data. There are accumulating evidences about the prominent regulatory role of specific phosphatases in cell cycle regulations. The current study emphasizes the possible role of multiple phosphatases that governs the cell cycle regulation in fission yeast S. pombe. The ability of the model to reproduce the reported regulatory profile for the wild-type and various mutants was verified though simulations. Electronic supplementary material: The online version of this article (doi:10.1007/s11693-011-9090-7) contains supplementary material, which is available to authorized users.
    Systems and Synthetic Biology 12/2011; 5(3-4):115-29. DOI:10.1007/s11693-011-9090-7
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    • "The question remains, however, why wild-type Spo13 cells, which undergo a reductional MI, execute a second M phase without first exiting division and initiating another round of DNA replication . We propose that Spo13 may be able to promote MII immediately after MI, by preventing the complete loss of Clb/Cdk activity and the A/exit transition (Queralt et al. 2006; Toth et al. 2007). Only after mitotic exit can prereplication complexes assemble to allow a subsequent round of DNA replication. "
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    ABSTRACT: Spo13 is a key meiosis-specific regulator required for centromere cohesion and coorientation, and for progression through two nuclear divisions. We previously reported that it causes a G2/M arrest and may delay the transition from late anaphase to G1, when overexpressed in mitosis. Yet its mechanism of action has remained elusive. Here we show that Spo13, which is phosphorylated and stabilized at G2/M in a Cdk/Clb-dependent manner, acts at two stages during mitotic cell division. Spo13 provokes a G2/M arrest that is reversible and largely independent of the Mad2 spindle checkpoint. Since mRNAs whose induction requires Cdc14 activation are reduced, we propose that its anaphase delay results from inhibition of Cdc14 function. Indeed, the Spo13-induced anaphase delay correlates with Cdc14 phosphatase retention in the nucleolus and with cyclin B accumulation, which both impede anaphase exit. At the onset of arrest, Spo13 is primarily associated with the nucleolus, where Cdc14 accumulates. Significantly, overexpression of separase (Esp1), which promotes G2/M and anaphase progression, suppresses Spo13 effects in mitosis, arguing that Spo13 acts upstream or parallel to Esp1. Given that Spo13 overexpression reduces Pds1 and cyclin B degradation, our findings are consistent with a role for Spo13 in regulating APC, which controls both G2/M and anaphase. Similar effects of Spo13 during meiotic MI may prevent cell cycle exit and initiation of DNA replication prior to MII, thereby ensuring two successive chromosome segregation events without an intervening S phase.
    Genetics 07/2010; 185(3):841-54. DOI:10.1534/genetics.109.113746 · 5.96 Impact Factor
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