Irreversibility of mitotic exit is the consequence of systems-level feedback

López-Avilés, Sandra; Kapuy, Orsolya; Novák, Béla; Uhlmann, Frank

doi:10.1038/nature07984

Cited by 94 publications

(104 citation statements)

References 30 publications

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“…Our data show that abrogation of Clp1-Cdc25 feedback reduces the abruptness of cytokinesis. Therefore, unlike S. cerevisiae Cdc14, which facilitates the mitotic exit switch at the metaphase-anaphase transition (13,14,36), S. pombe Clp1 controls the abruptness of the mitotic exit switch primarily by promoting proper SIN and contractile ring activity.…”

Section: Discussionmentioning

confidence: 99%

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Lu¹,

Domingo-Sananes

Huzarska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cyclin-dependent kinase 1 (Cdk1) kinase dephosphorylation and activation by Cdc25 phosphatase are essential for mitotic entry. Activated Cdk1 phosphorylates Cdc25 and other substrates, further activating Cdc25 to form a positive feedback loop that drives the abrupt G2/mitosis switch. Conversely, mitotic exit requires Cdk1 inactivation and reversal of Cdk1 substrate phosphorylation. This dephosphorylation is mediated, in part, by Clp1/Cdc14, a Cdk1-antagonizing phosphatase, which reverses Cdk1 phosphorylation of itself, Cdc25, and other Cdk1 substrates. Thus, Cdc25 phosphoregulation is essential for proper G2-M transition, and its contributions to cell cycle control have been modeled based on studies using Xenopus and human cell extracts. Because cell extract systems only approximate in vivo conditions where proteins interact within dynamic cellular environments, here, we use Schizosaccharomyces pombe to characterize, both experimentally and mathematically, the in vivo contributions of Cdk1-mediated phosphorylation of Cdc25 to the mitotic transition. Through comprehensive mapping of Cdk1 phosphosites on Cdc25 and characterization of phosphomutants, we show that Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation, the precision of mitotic entry, and unvarying cell length but not Cdc25 localization or abundance. We propose a mathematical model that explains Cdc25 regulation by Cdk1 through a distributive and disordered phosphorylation mechanism that ultrasensitively activates Cdc25. We also show that Clp1/Cdc14 dephosphorylation of Cdk1 sites on Cdc25 controls the proper timing of cell division, a mechanism that is likely due to the double negative feedback loop between Clp1/Cdc14 and Cdc25 that controls the abruptness of the mitotic exit switch. mitotic bistability | multisite phosphorylation

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Section: Discussionmentioning

confidence: 99%

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Lu¹,

Domingo-Sananes

Huzarska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, cyclin destruction is not sufficient for the irreversibility of mitotic exit in yeast. Instead, Sic1 accumulation and activation of APC/C by Cdc20 homologue 1 (Cdh1) build hysteresis into the mitotic exit network (López-Avilés et al, 2009). Hysteresis can, thus, be seen to rely on two mechanisms that have distinct regulation.…”

Section: Multiple Mechanisms Promote Hysteresis To Create Directionalitymentioning

confidence: 99%

Phosphorylation network dynamics in the control of cell cycle transitions

Fisher

Krasińska

Coudreuse

et al. 2012

Journal of Cell Science

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143

114

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SummaryFifteen years ago, it was proposed that the cell cycle in fission yeast can be driven by quantitative changes in the activity of a single protein kinase complex comprising a cyclin -namely cyclin B -and cyclin dependent kinase 1 (Cdk1). When its activity is low, Cdk1 triggers the onset of S phase; when its activity level exceeds a specific threshold, it promotes entry into mitosis. This model has redefined our understanding of the essential functional inputs that organize cell cycle progression, and its main principles now appear to be applicable to all eukaryotic cells. But how does a change in the activity of one kinase generate ordered progression through the cell cycle in order to separate DNA replication from mitosis? To answer this question, we must consider the biochemical processes that underlie the phosphorylation of Cdk1 substrates. In this Commentary, we discuss recent findings that have shed light on how the threshold levels of Cdk1 activity that are required for progression through each phase are determined, how an increase in Cdk activity generates directionality in the cell cycle, and why cell cycle transitions are abrupt rather than gradual. These considerations lead to a general quantitative model of cell cycle control, in which opposing kinase and phosphatase activities have an essential role in ensuring dynamic transitions.

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“…Its expression and activation during the M-to-G1 transition creates a negative feedback loop that makes mitotic exit an irreversible process (Luca et al 2001;Lopez-Aviles et al 2009;He et al 2011). Swi5 also drives the expression of the cell separation gene EGT2 and the transcriptional repressor ASH1, an mRNA that is transported to the daughter cell and ultimately translated there to suppress mating type switching.…”

Section: Regulation Of Septation Machinery and The Cytokinetic Apparatusmentioning

confidence: 99%

Mitotic Exit and Separation of Mother and Daughter Cells

2012

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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 parts 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.

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Irreversibility of mitotic exit is the consequence of systems-level feedback

Cited by 94 publications

References 30 publications

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Phosphorylation network dynamics in the control of cell cycle transitions

Mitotic Exit and Separation of Mother and Daughter Cells

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