A quantitative model for cyclin-dependent kinase control of the cell cycle: Revisited

Chromosome Segregation Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 12/2011; 366(1584):3572-83. DOI: 10.1098/rstb.2011.0082
Source: PubMed


The eukaryotic cell division cycle encompasses an ordered series of events. Chromosomal DNA is replicated during S phase of the cell cycle before being distributed to daughter cells in mitosis. Both S phase and mitosis in turn consist of an intricately ordered sequence of molecular events. How cell cycle ordering is achieved, to promote healthy cell proliferation and avert insults on genomic integrity, has been a theme of Paul Nurse's research. To explain a key aspect of cell cycle ordering, sequential S phase and mitosis, Stern & Nurse proposed 'A quantitative model for cdc2 control of S phase and mitosis in fission yeast'. In this model, S phase and mitosis are ordered by their dependence on increasing levels of cyclin-dependent kinase (Cdk) activity. Alternative mechanisms for ordering have been proposed that rely on checkpoint controls or on sequential waves of cyclins with distinct substrate specificities. Here, we review these ideas in the light of experimental evidence that has meanwhile accumulated. Quantitative Cdk control emerges as the basis for cell cycle ordering, fine-tuned by cyclin specificity and checkpoints. We propose a molecular explanation for quantitative Cdk control, based on thresholds imposed by Cdk-counteracting phosphatases, and discuss its implications.

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Available from: Sandra Lopez, Mar 17, 2014
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    • "Cdc14 is a cell cycle phosphatase essential for the mitosisto-G 1 transition in Saccharomyces cerevisiae, the end of the cell cycle (reviewed in Stegmeier and Amon 2004; De Wulf et al. 2009; Mocciaro and Schiebel 2010; Uhlmann et al. 2011; Wurzenberger and Gerlich 2011; Meitinger et al. 2012; Weiss 2012). This protein belongs to a superfamily of dual-specificity phosphatases highly conserved in all eukaryotes, although their roles seem to have diverged during evolution. "
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    ABSTRACT: Cycling events in nature start and end to restart again and again. In the cell cycle, whose purpose is to become two where there was only one, cyclin-dependent kinases (CDKs) are the beginning and, therefore, phosphatases must play a role in the ending. Since CDKs are drivers of the cell cycle and cancer cells uncontrollably divide, much attention has been put into knocking down CDK activity. However, much less is known on the consequences of interfering with the phosphatases that put an end to the cell cycle. We have addressed in recent years the consequences of transiently inactivating the only master cell cycle phosphatase in the model yeast Saccharomyces cerevisiae, Cdc14. Transient inactivation is expected to better mimic the pharmacological action of drugs. Interestingly, we have found that yeast cells tolerate badly a relatively brief inactivation of Cdc14 when cells are already committed into anaphase, the first cell cycle stage where this phosphatase plays important roles. First, we noticed that the segregation of distal regions in the chromosome arm that carries the ribosomal DNA array was irreversibly impaired, leading to an anaphase bridge (AB). Next, we found that this AB could eventually be severed by cytokinesis and led to two different types of genetically compromised daughter cells. All these previous studies were done in haploid cells. We have now recently expanded this analysis to diploid cells and used the advantage of making hybrid diploids to study chromosome rearrangements and changes in the ploidy of the surviving progeny. We have found that the consequences for the genome integrity were far more dramatic than originally envisioned.
    Current Genetics 06/2015; DOI:10.1007/s00294-015-0502-1 · 2.68 Impact Factor
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    • "Initiation of each phase of the cell cycle is dependent on the proper progression and completion of the previous one, ensuring a unidirectional progression through the cell cycle. How the progression through the phases of the cell cycle is achieved is still under investigation [10–12] but requires cyclin/Cdk complexes assisted by several protein kinases, including the mitotic kinases Polo and Aurora. "
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    ABSTRACT: Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression.
    Open Biology 08/2013; 3(8):130083. DOI:10.1098/rsob.130083 · 5.78 Impact Factor
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    • "Progress in the eukaryotic cell cycle is driven by protein kinase complexes consisting of cyclins and CDKs. CDK activity is regulated negatively by a group of proteins called CDK inhibitors, including the protein p21 and p27 [38]. In the present study, cyclin D1 was increased in p65-overexpressing cells even in the presence of celecoxib, and p65 overexpression caused the inhibition of p21, suggesting a possible protective role for p65 expression in celecoxib-mediated cell cycle arrest. "
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    ABSTRACT: Celecoxib is a selective cyclooxygenase (COX)-2 inhibitor that has been reported to reduce the risk of breast cancer. In our previous study, celecoxib induced apoptosis and caused cell cycle arrest at the G0/G1 phase in the breast cancer cell line MDA-MB-231, and its effects were mediated by downregulation of NF-κB signaling. The NF-κB p65/RelA subunit may play a role in cell death through the activation of anti-apoptotic target genes including the inhibitor of apoptosis (IAP) and Bcl-2 families, and inhibition of protein kinase B/Akt. The aim of the present study was to investigate p65 as the potential target of celecoxib treatment and determine whether p65 overexpression can override the inhibitory effect of celecoxib on NF-κB activity and affect cell survival. The effects of p65 overexpression on celecoxib-inhibited NF-κB transcriptional activity were examined by western blotting, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. Cell viability and cell death were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, and the levels of cleaved poly(ADP-ribose) polymerase (PARP) and caspase. Anti-apoptotic NF-κB target genes and cell cycle regulators were examined by western blotting to screen for the expression of target genes under direct regulation by p65. Overexpression of p65 increased NF-κB transcriptional activity and interfered with celecoxib-mediated apoptosis as assessed by MTT assay and caspase-3, caspase-9, and PARP expressions. Exogenously overexpressed p65 upregulated NF-κB-responsive genes, including anti-apoptotic genes such as survivin and XIAP, and the cell cycle regulatory gene cyclin D1. However, p65 overexpression did not affect celecoxib-induced p-Akt inactivation, suggesting that celecoxib might have separate molecular mechanisms for regulating Akt signaling independently of its inhibition of NF-κB transcriptional activity. p65 is a pivotal anti-apoptotic factor that can reverse celecoxib-induced growth inhibition in MDA-MB-231 cells.
    Cancer Cell International 02/2013; 13(1):14. DOI:10.1186/1475-2867-13-14 · 2.77 Impact Factor
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