scholarly journals Mathematical model of the morphogenesis checkpoint in budding yeast

2003 ◽  
Vol 163 (6) ◽  
pp. 1243-1254 ◽  
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.

scholarly journals Budding yeast relies on G1 cyclin specificity to couple cell cycle progression with morphogenetic development

2021 ◽  
Vol 7 (23) ◽  
pp. eabg0007
Author(s):  
Deniz Pirincci Ercan ◽  
Florine Chrétien ◽  
Probir Chakravarty ◽  
Helen R. Flynn ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Quantitative Model ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Model Cell ◽  
Mitotic Cyclin ◽  
Substrate Phosphorylation ◽  
The Cost

Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities of successive cyclin waves. Alternatively, in the quantitative model, the gradual rise of Cdk activity from G1 phase to mitosis leads to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in Saccharomyces cerevisiae. All S phase and mitotic cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. A single cyclin can also replace all G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot survive. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

scholarly journals Analysis of Cell Cycle Progression in the Budding Yeast S. cerevisiae

2021 ◽  
pp. 265-276
Author(s):  
Deniz Pirincci Ercan ◽  
Frank Uhlmann
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Expression Profiles ◽  
Model Organisms ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Daughter Cells ◽  
Substrate Phosphorylation

AbstractThe cell cycle is an ordered series of events by which cells grow and divide to give rise to two daughter cells. In eukaryotes, cyclin–cyclin-dependent kinase (cyclin–Cdk) complexes act as master regulators of the cell division cycle by phosphorylating numerous substrates. Their activity and expression profiles are regulated in time. The budding yeast S. cerevisiae was one of the pioneering model organisms to study the cell cycle. Its genetic amenability continues to make it a favorite model to decipher the principles of how changes in cyclin-Cdk activity translate into the intricate sequence of substrate phosphorylation events that govern the cell cycle. In this chapter, we introduce robust and straightforward methods to analyze cell cycle progression in S. cerevisiae. These techniques can be utilized to describe cell cycle events and to address the effects of perturbations on accurate and timely cell cycle progression.

scholarly journals The Gcn2 Regulator Yih1 Interacts with the Cyclin Dependent Kinase Cdc28 and Promotes Cell Cycle Progression through G2/M in Budding Yeast

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0131070 ◽  
Author(s):  
Richard C. Silva ◽  
Martina Dautel ◽  
Bruno M. Di Genova ◽  
David C. Amberg ◽  
Beatriz A. Castilho ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression

scholarly journals A Morphogenesis Checkpoint Monitors the Actin Cytoskeleton in Yeast

1998 ◽  
Vol 142 (6) ◽  
pp. 1487-1499 ◽  
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.

scholarly journals Phosphorylation-Independent Inhibition of Cdc28p by the Tyrosine Kinase Swe1p in the Morphogenesis Checkpoint

1999 ◽  
Vol 19 (9) ◽  
pp. 5981-5990 ◽  
Author(s):  
John N. McMillan ◽  
Rey A. L. Sia ◽  
Elaine S. G. Bardes ◽  
Daniel J. Lew
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Single Copy ◽  
Cyclin Dependent Kinase ◽  
Independent Manner ◽  
Cycle Progression ◽  
Checkpoint Response ◽  
Inhibitory Pathways ◽  
Morphogenesis Checkpoint

ABSTRACT The morphogenesis checkpoint in budding yeast delays cell cycle progression in G2 when the actin cytoskeleton is perturbed, providing time for cells to complete bud formation prior to mitosis. Checkpoint-induced G2 arrest involves the inhibition of the master cell cycle regulatory cyclin-dependent kinase, Cdc28p, by the Wee1 family kinase Swe1p. Results of experiments using a nonphosphorylatable CDC28Y19F allele suggested that the checkpoint stimulated two inhibitory pathways, one that promoted phosphorylation at tyrosine 19 (Y19) and a poorly characterized second pathway that did not require Cdc28p Y19 phosphorylation. We present the results from a genetic screen for checkpoint-defective mutants that led to the repeated isolation of the dominant CDC28E12K allele that is resistant to Swe1p-mediated inhibition. Comparison of this allele with the nonphosphorylatable CDC28Y19F allele suggested that Swe1p is still able to inhibit CDC28Y19F in a phosphorylation-independent manner and that both the Y19 phosphorylation-dependent and -independent checkpoint pathways in fact reflect Swe1p inhibition of Cdc28p. Remarkably, we found that a Swe1p mutant lacking catalytic activity could significantly delay the cell cycle in vivo during a physiological checkpoint response, even when expressed at single copy. The finding that a Wee1 family kinase expressed at physiological levels can inhibit a nonphosphorylatable cyclin-dependent kinase has broad implications for many checkpoint studies using such mutants in other organisms.

scholarly journals Cdc28 tyrosine phosphorylation and the morphogenesis checkpoint in budding yeast.

1996 ◽  
Vol 7 (11) ◽  
pp. 1657-1666 ◽  
Author(s):  
R A Sia ◽  
H A Herald ◽  
D J Lew
Keyword(s):  
Cell Cycle ◽  
Translational Regulation ◽  
Cell Cycle Progression ◽  
Nuclear Division ◽  
Budding Yeast ◽  
Mrna Levels ◽  
Gene Encoding ◽  
Cycle Progression ◽  
Morphogenesis Checkpoint ◽  
In Cells

A morphogenesis checkpoint in budding yeast delays nuclear division (and subsequent cell cycle progression) in cells that have failed to make a bud. We show that the ability of this checkpoint to delay nuclear division requires the SWE1 gene, encoding a protein kinase that inhibits the master cell cycle regulatory kinase Cdc28. The timing of nuclear division in cells that cannot make a bud is exquisitely sensitive to the dosage of SWE1 and MIH1 genes, which control phosphorylation of Cdc28 at tyrosine 19. In contrast, the timing of nuclear division in budded cells does not rely on Cdc28 phosphorylation, suggesting that the morphogenesis checkpoint somehow turns on this regulatory pathway. We show that SWE1 mRNA levels fluctuate during the cell cycle and are elevated in cells that cannot make a bud. However, regulation of SWE1 mRNA levels by the checkpoint is indirect, acting through a feedback loop requiring Swe1 activity. Further, the checkpoint is capable of delaying nuclear division even when SWE1 transcription is deregulated. We propose that the checkpoint delays nuclear division through post-translational regulation of Swe1 and that transcriptional feedback loops enhance the efficacy of the checkpoint.

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

1999 ◽  
Vol 19 (10) ◽  
pp. 6929-6939 ◽  
Author(s):  
John N. McMillan ◽  
Mark S. Longtine ◽  
Rey A. L. Sia ◽  
Chandra L. Theesfeld ◽  
Elaine S. G. Bardes ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Negative Regulators ◽  
Cycle Progression ◽  
Bud Formation ◽  
M Phase ◽  
Subsequent Degradation ◽  
Morphogenesis Checkpoint

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.

scholarly journals DNA Damage Checkpoints Inhibit Mitotic Exit by Two Different Mechanisms

2007 ◽  
Vol 27 (14) ◽  
pp. 5067-5078 ◽  
Author(s):  
Fengshan Liang ◽  
Yanchang Wang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Mitotic Exit ◽  
Yeast Cells ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Dna Damage Checkpoints ◽  
Early Anaphase

ABSTRACT Cyclin-dependent kinase (CDK) governs cell cycle progression, and its kinase activity fluctuates during the cell cycle. Mitotic exit pathways are responsible for the inactivation of CDK after chromosome segregation by promoting the release of a nucleolus-sequestered phosphatase, Cdc14, which antagonizes CDK. In the budding yeast Saccharomyces cerevisiae, mitotic exit is controlled by the FEAR (for “Cdc-fourteen early anaphase release”) and mitotic exit network (MEN) pathways. In response to DNA damage, two branches of the DNA damage checkpoint, Chk1 and Rad53, are activated in budding yeast to prevent anaphase entry and mitotic exit, allowing cells more time to repair damaged DNA. Here we present evidence indicating that yeast cells negatively regulate mitotic exit through two distinct pathways in response to DNA damage. Rad53 prevents mitotic exit by inhibiting the MEN pathway, whereas the Chk1 pathway prevents FEAR pathway-dependent Cdc14 release in the presence of DNA damage. In contrast to previous data, the Rad53 pathway negatively regulates MEN independently of Cdc5, a Polo-like kinase essential for mitotic exit. Instead, a defective Rad53 pathway alleviates the inhibition of MEN by Bfa1.

Cyclin specificity: how many wheels do you need on a unicycle?

2001 ◽  
Vol 114 (10) ◽  
pp. 1811-1820 ◽  
Author(s):  
M.E. Miller ◽  
F.R. Cross
Keyword(s):  
Cell Cycle ◽  
Subcellular Localization ◽  
Cell Cycle Progression ◽  
Eukaryotic Cell ◽  
Cyclin Dependent Kinase ◽  
Temporal Expression ◽  
Cycle Progression

Cyclin-dependent kinase (CDK) activity is essential for eukaryotic cell cycle events. Multiple cyclins activate CDKs in all eukaryotes, but it is unclear whether multiple cyclins are really required for cell cycle progression. It has been argued that cyclins may predominantly act as simple enzymatic activators of CDKs; in opposition to this idea, it has been argued that cyclins might target the activated CDK to particular substrates or inhibitors. Such targeting might occur through a combination of factors, including temporal expression, protein associations, and subcellular localization.

scholarly journals Molecular Evolution Allows Bypass of the Requirement for Activation Loop Phosphorylation of the Cdc28 Cyclin-Dependent Kinase

1998 ◽  
Vol 18 (5) ◽  
pp. 2923-2931 ◽  
Author(s):  
Frederick R. Cross ◽  
Kristi Levine
Keyword(s):  
Cell Cycle ◽  
Biological Activity ◽  
Cell Cycle Progression ◽  
Dna Amplification ◽  
Protein Kinase Activity ◽  
Activation Loop ◽  
Cyclin Dependent Kinase ◽  
High Biological Activity ◽  
Cycle Progression ◽  
Growth Defects

ABSTRACT Many protein kinases are regulated by phosphorylation in the activation loop, which is required for enzymatic activity. Glutamic acid can substitute for phosphothreonine in some proteins activated by phosphorylation, but this substitution (T169E) at the site of activation loop phosphorylation in the Saccharomyces cerevisiae cyclin-dependent kinase (Cdk) Cdc28p blocks biological function and protein kinase activity. Using cycles of error-prone DNA amplification followed by selection for successively higher levels of function, we identified mutant versions of Cdc28p-T169E with high biological activity. The enzymatic and biological activity of the mutant Cdc28p was essentially normally regulated by cyclin, and the mutants supported normal cell cycle progression and regulation. Therefore, it is not a requirement for control of the yeast cell cycle that Cdc28p be cyclically phosphorylated and dephosphorylated. TheseCDC28 mutants allow viability in the absence of Cak1p, the essential kinase that phosphorylates Cdc28p-T169, demonstrating that T169 phosphorylation is the only essential function of Cak1p. Some growth defects remain in suppressed cak1 cdc28 strains carrying the mutant CDC28 genes, consistent with additional nonessential roles for CAK1.

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