The Morphogenesis Checkpoint in Saccharomyces cerevisiae: Cell Cycle Control of Swe1p Degradation by Hsl1p and Hsl7p

ABSTRACT In Saccharomyces cerevisiae, the Wee1 family kinase Swe1p is normally stable during G1 and S phases but is unstable during G2 and M phases due to ubiquitination and subsequent degradation. However, perturbations of the actin cytoskeleton lead to a stabilization and accumulation of Swe1p. This response constitutes part of a morphogenesis checkpoint that couples cell cycle progression to proper bud formation, but the basis for the regulation of Swe1p degradation by the morphogenesis checkpoint remains unknown. Previous studies have identified a protein kinase, Hsl1p, and a phylogenetically conserved protein of unknown function, Hsl7p, as putative negative regulators of Swe1p. We report here that Hsl1p and Hsl7p act in concert to target Swe1p for degradation. Both proteins are required for Swe1p degradation during the unperturbed cell cycle, and excess Hsl1p accelerates Swe1p degradation in the G2-M phase. Hsl1p accumulates periodically during the cell cycle and promotes the periodic phosphorylation of Hsl7p. Hsl7p can be detected in a complex with Swe1p in cell lysates, and the overexpression of Hsl7p or Hsl1p produces an effective override of the G2arrest imposed by the morphogenesis checkpoint. These findings suggest that Hsl1p and Hsl7p interact directly with Swe1p to promote its recognition by the ubiquitination complex, leading ultimately to its destruction.

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Cell cycle control

Oxford Textbook of Oncology ◽

10.1093/med/9780199656103.003.0004 ◽

2016 ◽

pp. 31-41

Author(s):

Simon M. Carr ◽

Nicholas B. La Thangue

Keyword(s):

Cell Cycle ◽

Final Stage ◽

Cell Cycle Progression ◽

Cell Cycle Control ◽

Control Mechanisms ◽

Chromosomal Dna ◽

Cycle Progression ◽

M Phase ◽

Cellular Components ◽

Regulate Cell Cycle Progression

All cells arise by the division of existing cells in a highly regulated series of events known as the cell cycle. Whilst duplication of other cellular contents occurs throughout all stages of the cycle, chromosomal DNA is replicated only once at a stage known as S phase. Once this is complete, distribution of chromosomes and other cellular components occurs during the final stage of the cell cycle, known as M phase, or mitosis. The cell cycle is therefore regulated in a temporal fashion, so that entry into subsequent cell cycle stages only occurs once the previous stage has been completed. A number of signalling mechanisms monitor the integrity of cell cycle progression, and later cell cycle stages can be delayed if any errors need correction. This chapter gives an overview of the major control mechanisms that regulate cell cycle progression, and how these are circumvented during the onset of cancer.

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Cyclin C influences the timing of mitosis in fission yeast

Molecular Biology of the Cell ◽

10.1091/mbc.e16-11-0787 ◽

2017 ◽

Vol 28 (13) ◽

pp. 1738-1744 ◽

Cited By ~ 2

Author(s):

Gabor Banyai ◽

Zsolt Szilagyi ◽

Vera Baraznenok ◽

Olga Khorosjutina ◽

Claes M. Gustafsson

Keyword(s):

Cell Cycle ◽

Fission Yeast ◽

Rna Polymerase Ii ◽

Cell Cycle Progression ◽

Cell Cycle Control ◽

Mediator Complex ◽

Cycle Progression ◽

Cyclin C ◽

M Phase

The multiprotein Mediator complex is required for the regulated transcription of nearly all RNA polymerase II–dependent genes. Mediator contains the Cdk8 regulatory subcomplex, which directs periodic transcription and influences cell cycle progression in fission yeast. Here we investigate the role of CycC, the cognate cyclin partner of Cdk8, in cell cycle control. Previous reports suggested that CycC interacts with other cellular Cdks, but a fusion of CycC to Cdk8 reported here did not cause any obvious cell cycle phenotypes. We find that Cdk8 and CycC interactions are stabilized within the Mediator complex and the activity of Cdk8-CycC is regulated by other Mediator components. Analysis of a mutant yeast strain reveals that CycC, together with Cdk8, primarily affects M-phase progression but mutations that release Cdk8 from CycC control also affect timing of entry into S phase.

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Dominant Alleles of Saccharomyces cerevisiae CDC20 Reveal Its Role in Promoting Anaphase

Genetics ◽

10.1093/genetics/148.2.599 ◽

1998 ◽

Vol 148 (2) ◽

pp. 599-610

Author(s):

Eric J Schott ◽

M Andrew Hoyt

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Cell Cycle Progression ◽

Spindle Assembly Checkpoint ◽

Limiting Factor ◽

Mutant Form ◽

Loss Of Function ◽

Cycle Progression ◽

Inhibit Cell Cycle Progression ◽

M Phase

Abstract We identified an allele of Saccharomyces cerevisiae CDC20 that exhibits a spindle-assembly checkpoint defect. Previous studies indicated that loss of CDC20 function caused cell cycle arrest prior to the onset of anaphase. In contrast, CDC20-50 caused inappropriate cell cycle progression through M phase in the absence of mitotic spindle function. This effect of CDC20-50 was dominant over wild type and was eliminated by a second mutation causing loss of function, suggesting that it encodes an overactive form of Cdc20p. Overexpression of CDC20 was found to cause a similar checkpoint defect, causing bypass of the preanaphase arrest produced by either microtubule-depolymerizing compounds or MPS1 overexpression. CDC20 overexpression was also able to overcome the anaphase delay caused by high levels of the anaphase inhibitor Pds1p, but not a mutant form immune to anaphase-promoting complex- (APC-)mediated proteolysis. CDC20 overexpression was unable to promote anaphase in cells deficient in APC function. These findings suggest that Cdc20p is a limiting factor that promotes anaphase entry by antagonizing Pds1p. Cdc20p may promote the APC-dependent proteolytic degradation of Pds1p and other factors that act to inhibit cell cycle progression through mitosis.

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A Morphogenesis Checkpoint Monitors the Actin Cytoskeleton in Yeast

The Journal of Cell Biology ◽

10.1083/jcb.142.6.1487 ◽

1998 ◽

Vol 142 (6) ◽

pp. 1487-1499 ◽

Cited By ~ 114

Author(s):

John N. McMillan ◽

Rey A.L. Sia ◽

Daniel J. Lew

Keyword(s):

Cell Cycle ◽

Actin Cytoskeleton ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Bud Formation ◽

Actin Organization ◽

Cell Cycle Delay ◽

Dependent Cell ◽

Polarity Establishment ◽

Morphogenesis Checkpoint

A morphogenesis checkpoint in budding yeast delays cell cycle progression in response to perturbations of cell polarity that prevent bud formation (Lew, D.J., and S.I. Reed. 1995. J. Cell Biol. 129:739– 749). The cell cycle delay depends upon the tyrosine kinase Swe1p, which phosphorylates and inhibits the cyclin-dependent kinase Cdc28p (Sia, R.A.L., H.A. Herald, and D.J. Lew. 1996. Mol. Biol. Cell. 7:1657– 1666). In this report, we have investigated the nature of the defect(s) that trigger this checkpoint. A Swe1p- dependent cell cycle delay was triggered by direct perturbations of the actin cytoskeleton, even when polarity establishment functions remained intact. Furthermore, actin perturbation could trigger the checkpoint even in cells that had already formed a bud, suggesting that the checkpoint directly monitors actin organization, rather than (or in addition to) polarity establishment or bud formation. In addition, we show that the checkpoint could detect actin perturbations through most of the cell cycle. However, the ability to respond to such perturbations by delaying cell cycle progression was restricted to a narrow window of the cell cycle, delimited by the periodic accumulation of the checkpoint effector, Swe1p.

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Mathematical model of the morphogenesis checkpoint in budding yeast

The Journal of Cell Biology ◽

10.1083/jcb.200306139 ◽

2003 ◽

Vol 163 (6) ◽

pp. 1243-1254 ◽

Cited By ~ 62

Author(s):

Andrea Ciliberto ◽

Bela Novak ◽

John J. Tyson

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Budding Yeast ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Bud Formation ◽

Control Signals ◽

Potent Inhibition ◽

Morphogenesis Checkpoint ◽

Size Threshold

The morphogenesis checkpoint in budding yeast delays progression through the cell cycle in response to stimuli that prevent bud formation. Central to the checkpoint mechanism is Swe1 kinase: normally inactive, its activation halts cell cycle progression in G2. We propose a molecular network for Swe1 control, based on published observations of budding yeast and analogous control signals in fission yeast. The proposed Swe1 network is merged with a model of cyclin-dependent kinase regulation, converted into a set of differential equations and studied by numerical simulation. The simulations accurately reproduce the phenotypes of a dozen checkpoint mutants. Among other predictions, the model attributes a new role to Hsl1, a kinase known to play a role in Swe1 degradation: Hsl1 must also be indirectly responsible for potent inhibition of Swe1 activity. The model supports the idea that the morphogenesis checkpoint, like other checkpoints, raises the cell size threshold for progression from one phase of the cell cycle to the next.

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Cdk1-Mediated Phosphorylation of Human ATF7 at Thr-51 and Thr-53 Promotes Cell-Cycle Progression into M Phase

PLoS ONE ◽

10.1371/journal.pone.0116048 ◽

2014 ◽

Vol 9 (12) ◽

pp. e116048 ◽

Cited By ~ 11

Author(s):

Hitomi Hasegawa ◽

Kenichi Ishibashi ◽

Shoichi Kubota ◽

Chihiro Yamaguchi ◽

Ryuzaburo Yuki ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Cycle Progression ◽

M Phase

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Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling

Cells ◽

10.3390/cells10123327 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3327

Author(s):

Zhixiang Wang

Keyword(s):

Cell Cycle ◽

Growth Factor ◽

Signaling Pathways ◽

Tyrosine Kinases ◽

Cell Cycle Progression ◽

Phase Cell ◽

Growth Factor Signaling ◽

Cycle Progression ◽

M Phase

The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk–cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.

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Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

Molecular and Cellular Biology ◽

10.1128/mcb.25.13.5725-5737.2005 ◽

2005 ◽

Vol 25 (13) ◽

pp. 5725-5737 ◽

Cited By ~ 97

Author(s):

Kazuhiro Katayama ◽

Naoya Fujita ◽

Takashi Tsuruo

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Inhibitor ◽

Phosphorylation Site ◽

Cytoplasmic Localization ◽

M Cell ◽

Serine Threonine Kinase ◽

Cycle Progression ◽

M Phase ◽

Promote Cell Cycle Progression

ABSTRACT The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3θ but not 14-3-3β or -σ. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3θ binding and cytoplasmic localization of WEE1Hu.

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Cell Cycle-Dependence of Autophagic Activity and Inhibition of Autophagosome Formation at M Phase in Tobacco BY-2 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21239166 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9166

Author(s):

Shigeru Hanamata ◽

Takamitsu Kurusu ◽

Kazuyuki Kuchitsu

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Plant Cells ◽

Regulatory Mechanisms ◽

Cdk Inhibitor ◽

Autophagosome Formation ◽

Cycle Progression ◽

M Phase ◽

Cell Cycle Dependence ◽

Cycle Dependence

Autophagy is ubiquitous in eukaryotic cells and plays an essential role in stress adaptation and development by recycling nutrients and maintaining cellular homeostasis. However, the dynamics and regulatory mechanisms of autophagosome formation during the cell cycle in plant cells remain poorly elucidated. We here analyzed the number of autophagosomes during cell cycle progression in synchronized tobacco BY-2 cells expressing YFP-NtATG8a as a marker for the autophagosomes. Autophagosomes were abundant in the G2 and G1 phases of interphase, though they were much less abundant in the M and S phases. Autophagosomes drastically decreased during the G2/M transition, and the CDK inhibitor roscovitine inhibited the G2/M transition and the decrease in autophagosomes. Autophagosomes were rapidly increased by a proteasome inhibitor, MG-132. MG-132-induced autophagosome formation was also markedly lower in the M phases than during interphase. These results indicate that the activity of autophagosome formation is differently regulated at each cell cycle stage, which is strongly suppressed during mitosis.

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