scholarly journals Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1

2016 ◽  
Vol 27 (14) ◽  
pp. 2198-2212 ◽  
Author(s):  
Sebastian Höckner ◽  
Lea Neumann-Arnold ◽  
Wolfgang Seufert
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
Negative Control ◽  
Nuclear Localization Sequence ◽  
Phosphorylation Sites ◽  
Localization Sequence ◽  
Cdk Phosphorylation

The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at multiple sites. Budding yeast Cdh1 carries nine Cdk phosphorylation sites in its N-terminal regulatory domain, most or all of which contribute to inhibition. However, the precise role of individual sites has remained unclear. Here, we report that the Cdk phosphorylation sites of yeast Cdh1 are organized into autonomous subgroups and act through separate mechanisms. Cdk sites 1–3 had no direct effect on the APC/C binding of Cdh1 but inactivated a bipartite nuclear localization sequence (NLS) and thereby controlled the partitioning of Cdh1 between cytoplasm and nucleus. In contrast, Cdk sites 4–9 did not influence the cell cycle–regulated localization of Cdh1 but prevented its binding to the APC/C. Cdk sites 4–9 reside near two recently identified APC/C interaction motifs in a pattern conserved with the human Cdh1 orthologue. Thus a Cdk-inhibited NLS goes along with Cdk-inhibited APC/C binding sites in yeast Cdh1 to relay the negative control by Cdk1 phosphorylation of the ubiquitin ligase APC/C-Cdh1.

scholarly journals Quantitative Characterization of a Mitotic Cyclin Threshold Regulating Exit from Mitosis

2005 ◽  
Vol 16 (5) ◽  
pp. 2129-2138 ◽  
Author(s):  
Frederick R. Cross ◽  
Lea Schroeder ◽  
Martin Kruse ◽  
Katherine C. Chen
Keyword(s):  
Cell Cycle ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Predictive Ability ◽  
Eukaryotic Cell ◽  
Model Predictions ◽  
Mitotic Cyclin ◽  
Constitutive Overexpression

Regulation of cyclin abundance is central to eukaryotic cell cycle control. Strong overexpression of mitotic cyclins is known to lock the system in mitosis, but the quantitative behavior of the control system as this threshold is approached has only been characterized in the in vitro Xenopus extract system. Here, we quantitate the threshold for mitotic block in budding yeast caused by constitutive overexpression of the mitotic cyclin Clb2. Near this threshold, the system displays marked loss of robustness, in that loss or even heterozygosity for some regulators becomes deleterious or lethal, even though complete loss of these regulators is tolerated at normal cyclin expression levels. Recently, we presented a quantitative kinetic model of the budding yeast cell cycle. Here, we use this model to generate biochemical predictions for Clb2 levels, asynchronous as well as through the cell cycle, as the Clb2 overexpression threshold is approached. The model predictions compare well with biochemical data, even though no data of this type were available during model generation. The loss of robustness of the Clb2 overexpressing system is also predicted by the model. These results provide strong confirmation of the model's predictive ability.

scholarly journals Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Matteo Barberis
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Current Knowledge ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
Quantitative Model ◽  
Forkhead Transcription Factors ◽  
Dynamic Coordination ◽  
Cell Cycle Dynamics

AbstractNetworks of interacting molecules organize topology, amount, and timing of biological functions. Systems biology concepts required to pin down ‘network motifs’ or ‘design principles’ for time-dependent processes have been developed for the cell division cycle, through integration of predictive computer modeling with quantitative experimentation. A dynamic coordination of sequential waves of cyclin-dependent kinases (cyclin/Cdk) with the transcription factors network offers insights to investigate how incompatible processes are kept separate in time during the eukaryotic cell cycle. Here this coordination is discussed for the Forkhead transcription factors in light of missing gaps in the current knowledge of cell cycle control in budding yeast. An emergent design principle is proposed where cyclin waves are synchronized by a cyclin/Cdk-mediated feed-forward regulation through the Forkhead as a transcriptional timer. This design is rationalized by the bidirectional interaction between mitotic cyclins and the Forkhead transcriptional timer, resulting in an autonomous oscillator that may be instrumental for a well-timed progression throughout the cell cycle. The regulation centered around the cyclin/Cdk–Forkhead axis can be pivotal to timely coordinate cell cycle dynamics, thereby to actuate the quantitative model of Cdk control.

scholarly journals Insights into the cellular mechanism of the yeast ubiquitin ligase APC/C-Cdh1 from the analysis of in vivo degrons

2015 ◽  
Vol 26 (5) ◽  
pp. 843-858 ◽  
Author(s):  
Lea Arnold ◽  
Sebastian Höckner ◽  
Wolfgang Seufert
Keyword(s):  
Nuclear Localization ◽  
Ubiquitin Ligase ◽  
Budding Yeast ◽  
Cellular Mechanism ◽  
Nuclear Localization Sequence ◽  
Localization Sequence ◽  
In Vivo Analysis ◽  
Spatiotemporal Control

In vivo analysis in budding yeast identifies APC/C-Cdh1–specific minimal degrons carrying either a D or a KEN box and a nuclear localization sequence. APC/C-Cdh1 activity is restricted to the nucleus, maximal in the nucleoplasm, and absent from the cytoplasm, allowing for spatiotemporal control of Cdh1 substrate proteolysis.

Eukaryotic Cell-Cycle Control

1992 ◽  
Vol 20 (2) ◽  
pp. 239-242 ◽  
Author(s):  
Paul Nurse
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Eukaryotic Cell

scholarly journals Computational modelling of mitotic exit in budding yeast: the role of separase and Cdc14 endocycles

2011 ◽  
Vol 8 (61) ◽  
pp. 1128-1141 ◽  
Author(s):  
P. K. Vinod ◽  
Paula Freire ◽  
Ahmed Rattani ◽  
Andrea Ciliberto ◽  
Frank Uhlmann ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Computational Modelling ◽  
Eukaryotic Cell ◽  
Mitotic Exit ◽  
Intuitive Reasoning ◽  
Systematic Analysis ◽  
Systems View

The operating principles of complex regulatory networks are best understood with the help of mathematical modelling rather than by intuitive reasoning. Hereby, we study the dynamics of the mitotic exit (ME) control system in budding yeast by further developing the Queralt's model. A comprehensive systems view of the network regulating ME is provided based on classical experiments in the literature. In this picture, Cdc20–APC is a critical node controlling both cyclin (Clb2 and Clb5) and phosphatase (Cdc14) branches of the regulatory network. On the basis of experimental situations ranging from single to quintuple mutants, the kinetic parameters of the network are estimated. Numerical analysis of the model quantifies the dependence of ME control on the proteolytic and non-proteolytic functions of separase. We show that the requirement of the non-proteolytic function of separase for ME depends on cyclin-dependent kinase activity. The model is also used for the systematic analysis of the recently discovered Cdc14 endocycles. The significance of Cdc14 endocycles in eukaryotic cell cycle control is discussed as well.

scholarly journals From START to FINISH: computational analysis of cell cycle control in budding yeast

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Pavel Kraikivski ◽  
Katherine C Chen ◽  
Teeraphan Laomettachit ◽  
T M Murali ◽  
John J Tyson
Keyword(s):  
Cell Cycle ◽  
Computational Analysis ◽  
Budding Yeast ◽  
Cell Cycle Control

Cdk1-Dependent Phosphorylation ofNPM Overrides G2/M Checkpoint and Increases Leukemic Blasts in Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1322-1322
Author(s):  
Wei Du ◽  
Yun Zhou ◽  
Suzette Pike ◽  
Qishen Pang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Xenograft Model ◽  
Phosphorylation Sites ◽  
M Cell ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Cycle Arrest ◽  
Regulation Of Cell Cycle

Abstract An elevated level of nucleophosmin (NPM) is often found in actively proliferative cells including human tumors. To identify the regulatory role for NPM phosphorylation in proliferation and cell cycle control, a series of mutants targeting the consensus cyclin-dependent kinase (CKD) phosphorylation sites was created to mimic or abrogate either single-site or multi-site phosphorylation. Cells expressing the phosphomimetic NPM mutants showed enhanced proliferation and G2/M cell-cycle transition; whereas nonphosphorylatable mutants induced G2/M cell-cycle arrest. Simultaneous inactivation of two CKD phosphorylation sites at Ser10 and Ser70 (S10A/S70A, NPM-AA) induced phosphorylation of Cdk1 at Tyr15 (Cdc2Tyr15) and increased cytoplasmic accumulation of Cdc25C. Strikingly, stress-induced Cdk1Tyr15 and Cdc25C sequestration were completely suppressed by expression of a double phosphomimetic NPM mutant (S10E/S70E, NPM-EE). Further analysis revealed that phosphorylation of NPM at both Ser10 and Ser70 sites were required for proper interaction between Cdk1 and Cdc25C in mitotic cells. Moreover, the NPM-EE mutant directly bound to Cdc25C and prevented phosphorylation of Cdc25C at Ser216 during mitosis. Finally, NPM-EE overrided stress-induced G2/M arrest, increased peripheral-blood blasts and splenomegaly in a NOD/SCID xenograft model, and promoted leukemia development in Fanconi mouse hematopoietic stem/progenitor cells. Thus, these findings reveal a novel function of NPM on regulation of cell-cycle progression, in which Cdk1-dependent phosphorylation of NPM controls cell-cycle progression at G2/M transition through modulation of Cdc25C activity.

scholarly journals Two distinct ubiquitin-proteolysis pathways in the fission yeast cell cycle

1999 ◽  
Vol 354 (1389) ◽  
pp. 1551-1557 ◽  
Author(s):  
Takashi Toda ◽  
Itziar Ochotorena ◽  
Kin-ichiro Kominami
Keyword(s):  
Cell Cycle ◽  
Fission Yeast ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Repeat Proteins ◽  
Cycle Dependent ◽  
Universal Mechanism

The SCF complex (Skp1-Cullin-1-F-box) and the APC/cyclosome (anaphase-promoting complex) are two ubiquitin ligases that play a crucial role in eukaryotic cell cycle control. In fission yeast F-box/WD-repeat proteins Pop1 and Pop2, components of SCF are required for cell-cycle-dependent degradation of the cyclin-dependent kinase (CDK) inhibitor Rum1 and the S-phase regulator Cdc18. Accumulation of these proteins in pop1 and pop2 mutants leads to re-replication and defects in sexual differentiation. Despite structural and functional similarities, Pop1 and Pop2 are not redundant homologues. Instead, these two proteins form heterodimers as well as homodimers, such that three distinct complexes, namely SCF Pop1/Pop1 , SCF Pop1/Pop2 and SCF Pop2/Pop2 , appear to exist in the cell. The APC/cyclosome is responsible for inactivation of CDK/cyclins through the degradation of B-type cyclins. We have identified two novel components or regulators of this complex, called Apc10 and Ste9, which are evolutionarily highly conserved. Apc10 (and Ste9), together with Rum1, are required for the establishment of and progression through the G1 phase in fission yeast. We propose that dual downregulation of CDK, one via the APC/cyclosome and the other via the CDK inhibitor, is a universal mechanism that is used to arrest the cell cycle at G1.

Genetic control of mitosis, meiosis and cellular differentiation during mammalian spermatogenesis

1995 ◽  
Vol 7 (4) ◽  
pp. 669 ◽  
Author(s):  
DJ Wolgemuth ◽  
K Rhee ◽  
S Wu ◽  
SE Ravnik
Keyword(s):  
Cell Cycle ◽  
Genetic Control ◽  
Current Knowledge ◽  
Cell Cycle Control ◽  
Mitotic Cell ◽  
Eukaryotic Cell ◽  
Model Systems ◽  
Regulatory Processes ◽  
Mammalian Cell Lines ◽  
Unique Cell

Gametogenesis in both the male and female mammal represents a specialized and highly regulated series of cell cycle events, involving both mitosis and meiosis as well as subsequent differentiation. Recent advances in our understanding of the genetic control of the eukaryotic cell cycle have underscored the evolutionarily-conserved nature of these regulatory processes. However, most of the data have been obtained from yeast model systems and mammalian cell lines. Furthermore, most of the observations focus on regulation of mitotic cell cycles. In the present paper: (i) aspects of gametogenesis in mammals that represent unique cell-cycle control points are highlighted; (ii) current knowledge on the regulation of the germ cell cycle, in the context of what is known in yeast and other model eukaryotic systems, is summarized; and (iii) strategies that can be used to identify additional cell cycle regulating genes are outlined.

scholarly journals Budding yeast Dma1 and Dma2 participate in regulation of Swe1 levels and localization

2011 ◽  
Vol 22 (13) ◽  
pp. 2185-2197 ◽  
Author(s):  
Erica Raspelli ◽  
Corinne Cassani ◽  
Giovanna Lucchini ◽  
Roberta Fraschini
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Replication Stress ◽  
Down Regulation ◽  
Evolutionarily Conserved ◽  
Dna Replication Stress ◽  
Morphogenesis Checkpoint ◽  
The One

Timely down-regulation of the evolutionarily conserved protein kinase Swe1 plays an important role in cell cycle control, as Swe1 can block nuclear division through inhibitory phosphorylation of the catalytic subunit of cyclin-dependent kinase. In particular, Swe1 degradation is important for budding yeast cell survival in case of DNA replication stress, whereas it is inhibited by the morphogenesis checkpoint in response to alterations in actin cytoskeleton or septin structure. We show that the lack of the Dma1 and Dma2 ubiquitin ligases, which moderately affects Swe1 localization and degradation during an unperturbed cell cycle with no apparent phenotypic effects, is toxic for cells that are partially defective in Swe1 down-regulation. Moreover, Swe1 is stabilized, restrained at the bud neck, and hyperphosphorylated in dma1Δ dma2Δ cells subjected to DNA replication stress, indicating that the mechanism stabilizing Swe1 under these conditions is different from the one triggered by the morphogenesis checkpoint. Finally, the Dma proteins are required for proper Swe1 ubiquitylation. Taken together, the data highlight a previously unknown role of these proteins in the complex regulation of Swe1 and suggest that they might contribute to control, directly or indirectly, Swe1 ubiquitylation.

Sign in / Sign up

Export Citation Format

Share Document