Gérard - 2019 - Coupling the cell cycle and the cell transformation networks (SBML)
Ontology highlight
ABSTRACT:
SUBMITTER: 
Didier Gonze
PROVIDER: MODEL1906070001 | BioModels | 2019-07-02
REPOSITORIES: BioModels
Similar Datasets
Project description:In the quantitative model for cell cycle control, progression from G1 through S phase and into mitosis is ordered by thresholds of increasing cyclin-dependent kinase (Cdk) activity. How such thresholds are read out by substrates, that respond with the correct phosphorylation timing, if not known. In budding yeast, Cdk phosphorylates its many substrates with widely varying efficiencies, but there is no obvious correlation between phosphorylation efficiency and timing. Instead, we explore here whether Cdk-counteracting phosphatases impose Cdk thresholds. We find that the abundant PP2ACdc55 phosphatase counteracts Cdk phosphorylation in interphase and delays phosphorylation of late Cdk substrates, an effect that is independent of its known impact on the Cdk tyrosine phosphorylation status. Strikingly, PP2ACdc55 specifically counteracts phosphorylation of threonine residues. Consequently, we find that threonine-directed phosphorylation occurs late in the cell cycle, compared to serine phosphorylation. Late phosphorylation of Ndd1, a model substrate, depends on threonine identity. Our results support a model in which phosphatases contribute to ordering cell cycle progression by directly counteracting Cdk phosphorylation and unveil a principle of cell cycle control based on the phosphoacceptor amino acid.
2017-01-23 | PXD004461 | Pride
Project description:The appropriate ordering of the cell cycle events in eukaryoates is thought to be brought about by qualitative differences in the substrate specificity of multiple differentially expression Cyclin-CDK complexes. Our analysis of fission yeast supports an alternative quantitative model. Here we report a phosphoproteomics based global analysis of CDK substrate phosphorylation. We show that the phosphorylation of different CDK substrates is precisely ordered during the cell cycle by a single Cyclin-CDK complex. This is achieved by the differential sensitivity of substrates to a progressively rising CDK-to-phosphatase activity ratio, with early-phosphorylated substrates more sensitive to CDK activity than late substrates. This is combined with a rapid substrate phosphorylation turnover to generate clearly resolved substrate-specific thresholds, which in turn ensures the temporal ordering of downstream cell cycle events. These observations can also explain the major genetic redundancies between different cyclins and CDKs in higher eukaryotes.
2018-04-11 | PXD003598 | Pride
Project description:Yeast cell cycle transcript dynamics in three S. cerevisiae strains grown at 30 degrees Celsius: cdc20 GALL-CDC20 (persistent mitotic CDK activity; CDK on), cdc8-ts (DNA replication checkpoint), GAL-cse4-353 (spindle assembly checkpoint), cdc8-ts cdc20 (DNA replication checkpoint, CDK on), and cdc8-ts cdc20, rad53-1 (DNA replication checkpoint without Rad53 activity, CDK on) in a BF264-15DU background. We compared transcript levels of genes previously shown to be periodically expressed in wild-type cells and in cells lacking all mitotic cyclins (clb1,2,3,4,5,6; CDK off). Two replicate time courses for each of the strains studied are included
2014-07-27 | E-GEOD-49650 | biostudies-arrayexpress
Project description:Yeast cell cycle transcript dynamics in three S. cerevisiae strains grown at 30 degrees Celsius: cdc20 GALL-CDC20 (persistent mitotic CDK activity; CDK on), cdc8-ts (DNA replication checkpoint), GAL-cse4-353 (spindle assembly checkpoint), cdc8-ts cdc20 (DNA replication checkpoint, CDK on), and cdc8-ts cdc20, rad53-1 (DNA replication checkpoint without Rad53 activity, CDK on) in a BF264-15DU background. We compared transcript levels of genes previously shown to be periodically expressed in wild-type cells and in cells lacking all mitotic cyclins (clb1,2,3,4,5,6; CDK off).
2014-07-27 | GSE49650 | GEO
Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.
2022-10-31 | GSE196137 | GEO
Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.
2022-10-31 | GSE196139 | GEO
Project description: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 associated with successive waves of G1, S and mitotic cyclins. Alternatively, the gradual quantitative rise of Cdk activity from G1 phase to mitosis could lead to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in the budding yeast S. cerevisiae. S-phase cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. The single cyclin can in addition replace 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 sustain proliferation. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.
2021-08-23 | PXD022757 | Pride
Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria parasites express ancestral CDKs and cyclins, whose functions and interdependency remain elusive. Here, we show that the unique Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It is essential for DNA replication and phosphorylates canonical S/TPxK CDK motifs on components of the pre-replicative complex otherwise regulated by distinct kinases in other eukaryotes. Over a replicative cycle, CRK5 stably interacts with a single Haemosporidia-specific cyclin (SOC2) with no evidence of SOC2 degradation. Regulation of CRK5 activity relies instead on dynamic phosphorylation of a C-terminus extension that mediates its interaction with SOC2. Our results present evidence that during the atypical cell cycles of Plasmodium gametogony, a unique and divergent cyclin/CDK pair fulfils the functional space of multiple eukaryotic cell-cycle kinases to initiate DNA replication.
2020-02-18 | PXD017283 | Pride
Project description:We propose an integrated computational model for the network of cyclin-dependent kinases (Cdks) that controls the dynamics of the mammalian cell cycle. The model contains four Cdk modules regulated by reversible phosphorylation, Cdk inhibitors, and protein synthesis or degradation. Growth factors (GFs) trigger the transition from a quiescent, stable steady state to self-sustained oscillations in the Cdk network. These oscillations correspond to the repetitive, transient activation of cyclin D/Cdk4-6 in G(1), cyclin E/Cdk2 at the G(1)/S transition, cyclin A/Cdk2 in S and at the S/G(2) transition, and cyclin B/Cdk1 at the G(2)/M transition. The model accounts for the following major properties of the mammalian cell cycle: (i) repetitive cell cycling in the presence of suprathreshold amounts of GF; (ii) control of cell-cycle progression by the balance between antagonistic effects of the tumor suppressor retinoblastoma protein (pRB) and the transcription factor E2F; and (iii) existence of a restriction point in G(1), beyond which completion of the cell cycle becomes independent of GF. The model also accounts for endoreplication. Incorporating the DNA replication checkpoint mediated by kinases ATR and Chk1 slows down the dynamics of the cell cycle without altering its oscillatory nature and leads to better separation of the S and M phases. The model for the mammalian cell cycle shows how the regulatory structure of the Cdk network results in its temporal self-organization, leading to the repetitive, sequential activation of the four Cdk modules that brings about the orderly progression along cell-cycle phases.
2019-06-28 | BIOMD0000000730 | BioModels
Project description:Transcript dynamics in the S. cerevisiae BF264-15D strains with genetically perturbed TFN or CDK-APC/C components. We compared the extents to which the programs of cell-cycle transcription were initiated during various cell-cycle arrests.
2019-01-31 | GSE75694 | GEO