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  1. Article ; Online: The bistable mitotic switch in fission yeast.

    Novák, Béla / Tyson, John J

    Molecular biology of the cell

    2024  , Page(s) mbcE24030142

    Abstract: In favorable conditions, eukaryotic cells proceed irreversibly through the cell division cycle (G1-S-G2-M) in order to produce two daughter cells with the same number and identity of chromosomes of their progenitor. The integrity of this process is ... ...

    Abstract In favorable conditions, eukaryotic cells proceed irreversibly through the cell division cycle (G1-S-G2-M) in order to produce two daughter cells with the same number and identity of chromosomes of their progenitor. The integrity of this process is maintained by 'checkpoints' that hold a cell at particular transition points of the cycle until all requisite events are completed. The crucial functions of these checkpoints seem to depend on irreversible bistability of the underlying checkpoint control systems. Bistability of cell cycle transitions has been confirmed experimentally in frog egg extracts, budding yeast cells and mammalian cells. For fission yeast cells, a recent paper by Patterson et al. (2021) provides experimental evidence for an abrupt transition from G2 phase into mitosis, and we show that these data are consistent with a stochastic model of a bistable switch governing the G2/M checkpoint. Interestingly, our model suggests that their experimental data could also be explained by a reversible/sigmoidal switch, and stochastic simulations confirm this supposition. We propose a simple modification of their experimental protocol that could provide convincing evidence for (or against) bistability of the G2/M transition in fission yeast.
    Language English
    Publishing date 2024-04-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E24-03-0142
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Book: Die Landnahme von Torre Bela

    Novak, Helga M

    Prosa

    (Rotbuch ; 150)

    1976  

    Author's details Helga M. Novak
    Series title Rotbuch ; 150
    Language German
    Size 70 S.
    Edition 1. - 5. Tsd.
    Publisher Rotbuch Verl
    Publishing place Berlin
    Document type Book
    ISBN 3880221502 ; 9783880221505
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  3. Article: Time-keeping and decision-making in the cell cycle.

    Tyson, John J / Novák, Béla

    Interface focus

    2022  Volume 12, Issue 4, Page(s) 20210075

    Abstract: Cell growth, DNA replication, mitosis and division are the fundamental processes by which life is passed on from one generation of eukaryotic cells to the next. The eukaryotic cell cycle is intrinsically a periodic process but not so much a 'clock' as a ' ...

    Abstract Cell growth, DNA replication, mitosis and division are the fundamental processes by which life is passed on from one generation of eukaryotic cells to the next. The eukaryotic cell cycle is intrinsically a periodic process but not so much a 'clock' as a 'copy machine', making new daughter cells as warranted. Cells growing under ideal conditions divide with clock-like regularity; however, if they are challenged with DNA-damaging agents or mitotic spindle disrupters, they will not progress to the next stage of the cycle until the damage is repaired. These 'decisions' (to exit and re-enter the cell cycle) are essential to maintain the integrity of the genome from generation to generation. A crucial challenge for molecular cell biologists in the 1990s was to unravel the genetic and biochemical mechanisms of cell cycle control in eukaryotes. Central to this effort were biochemical studies of the clock-like regulation of 'mitosis promoting factor' during synchronous mitotic cycles of fertilized frog eggs and genetic studies of the switch-like regulation of 'cyclin-dependent kinases' in yeast cells. In this review, we uncover some secrets of cell cycle regulation by mathematical modelling of increasingly more complex molecular regulatory networks of cell cycle 'clocks' and 'switches'.
    Language English
    Publishing date 2022-06-10
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2042-8898
    ISSN 2042-8898
    DOI 10.1098/rsfs.2021.0075
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Computational modeling of chromosome re-replication in mutant strains of fission yeast.

    Novák, Béla / Tyson, John J

    Molecular biology of the cell

    2021  Volume 32, Issue 9, Page(s) 830–841

    Abstract: Typically cells replicate their genome only once per division cycle, but under some circumstances, both natural and unnatural, cells synthesize an overabundance of DNA, either in a disorganized manner ("overreplication") or by a systematic doubling of ... ...

    Abstract Typically cells replicate their genome only once per division cycle, but under some circumstances, both natural and unnatural, cells synthesize an overabundance of DNA, either in a disorganized manner ("overreplication") or by a systematic doubling of chromosome number ("endoreplication"). These variations on the theme of DNA replication and division have been studied in strains of fission yeast,
    MeSH term(s) CDC2 Protein Kinase/metabolism ; Cell Cycle ; Cell Cycle Proteins/metabolism ; Chromosomes/metabolism ; Computational Biology/methods ; Cyclin B/metabolism ; Cyclin-Dependent Kinases/metabolism ; Cyclins/metabolism ; DNA/metabolism ; DNA Replication ; DNA Replication Timing/genetics ; Models, Theoretical ; Phosphorylation ; Schizosaccharomyces/genetics ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism
    Chemical Substances Cdc13 protein, S pombe ; Cell Cycle Proteins ; Cyclin B ; Cyclins ; Schizosaccharomyces pombe Proteins ; cdc18 protein, S pombe ; DNA (9007-49-2) ; CDC2 Protein Kinase (EC 2.7.11.22) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
    Language English
    Publishing date 2021-02-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E20-09-0610
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Mechanisms of signalling-memory governing progression through the eukaryotic cell cycle.

    Novák, Béla / Tyson, John J

    Current opinion in cell biology

    2021  Volume 69, Page(s) 7–16

    Abstract: As cells pass through each replication-division cycle, they must be able to postpone further progression if they detect any threats to genome integrity, such as DNA damage or misaligned chromosomes. Once a 'decision' is made to proceed, the cell ... ...

    Abstract As cells pass through each replication-division cycle, they must be able to postpone further progression if they detect any threats to genome integrity, such as DNA damage or misaligned chromosomes. Once a 'decision' is made to proceed, the cell unequivocally enters into a qualitatively different biochemical state, which makes the transitions from one cell cycle phase to the next switch-like and irreversible. Each transition is governed by a unique signalling network; nonetheless, they share a common characteristic of bistable behaviour, a hallmark of molecular memory devices. Comparing the cell cycle signalling mechanisms acting at the restriction point, G1/S, G2/M and meta-to-anaphase transitions, we deduce a generic network motif of coupled positive and negative feedback loops underlying each transition.
    MeSH term(s) Cell Cycle ; Cell Cycle Proteins/metabolism ; DNA Damage ; Eukaryotic Cells/metabolism ; Signal Transduction
    Chemical Substances Cell Cycle Proteins
    Language English
    Publishing date 2021-01-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1026381-0
    ISSN 1879-0410 ; 0955-0674
    ISSN (online) 1879-0410
    ISSN 0955-0674
    DOI 10.1016/j.ceb.2020.12.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The oscillation of mitotic kinase governs cell cycle latches in mammalian cells.

    Dragoi, Calin-Mihai / Kaur, Ekjot / Barr, Alexis R / Tyson, John J / Novák, Béla

    Journal of cell science

    2024  Volume 137, Issue 3

    Abstract: The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase ...

    Abstract The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 'endocycles', and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.
    MeSH term(s) Animals ; Cell Cycle ; Anaphase-Promoting Complex-Cyclosome/metabolism ; Cell Cycle Proteins/metabolism ; Cyclins ; Cyclin-Dependent Kinases/metabolism ; Mitosis ; Cdc20 Proteins/metabolism ; Mammals/metabolism
    Chemical Substances Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27) ; Cell Cycle Proteins ; Cyclins ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; Cdc20 Proteins
    Language English
    Publishing date 2024-02-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.261364
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Mitotic kinase oscillation governs the latching of cell cycle switches.

    Novak, Bela / Tyson, John J

    Current biology : CB

    2022  Volume 32, Issue 12, Page(s) 2780–2785.e2

    Abstract: In 1996, Kim ... ...

    Abstract In 1996, Kim Nasmyth
    MeSH term(s) Cell Cycle ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Mitosis ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomycetales/metabolism
    Chemical Substances Cell Cycle Proteins ; Saccharomyces cerevisiae Proteins ; Cyclin-Dependent Kinases (EC 2.7.11.22)
    Language English
    Publishing date 2022-05-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2022.04.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Pom1 is not the size ruler.

    Novák, Béla

    Cell cycle (Georgetown, Tex.)

    2013  Volume 12, Issue 22, Page(s) 3463–3464

    MeSH term(s) Protein Kinases/metabolism ; Schizosaccharomyces/metabolism
    Chemical Substances Protein Kinases (EC 2.7.-)
    Language English
    Publishing date 2013-10-15
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.26818
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Reusable rule-based cell cycle model explains compartment-resolved dynamics of 16 observables in RPE-1 cells.

    Lang, Paul F / Penas, David R / Banga, Julio R / Weindl, Daniel / Novak, Bela

    PLoS computational biology

    2024  Volume 20, Issue 1, Page(s) e1011151

    Abstract: The mammalian cell cycle is regulated by a well-studied but complex biochemical reaction system. Computational models provide a particularly systematic and systemic description of the mechanisms governing mammalian cell cycle control. By combining both ... ...

    Abstract The mammalian cell cycle is regulated by a well-studied but complex biochemical reaction system. Computational models provide a particularly systematic and systemic description of the mechanisms governing mammalian cell cycle control. By combining both state-of-the-art multiplexed experimental methods and powerful computational tools, this work aims at improving on these models along four dimensions: model structure, validation data, validation methodology and model reusability. We developed a comprehensive model structure of the full cell cycle that qualitatively explains the behaviour of human retinal pigment epithelial-1 cells. To estimate the model parameters, time courses of eight cell cycle regulators in two compartments were reconstructed from single cell snapshot measurements. After optimisation with a parallel global optimisation metaheuristic we obtained excellent agreements between simulations and measurements. The PEtab specification of the optimisation problem facilitates reuse of model, data and/or optimisation results. Future perturbation experiments will improve parameter identifiability and allow for testing model predictive power. Such a predictive model may aid in drug discovery for cell cycle-related disorders.
    MeSH term(s) Humans ; Animals ; Cell Division ; Cell Cycle ; Neurons ; Drug Discovery ; Research Design ; Mammals
    Language English
    Publishing date 2024-01-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1011151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Reusable rule-based cell cycle model explains compartment-resolved dynamics of 16 observables in RPE-1 cells.

    Paul F Lang / David R Penas / Julio R Banga / Daniel Weindl / Bela Novak

    PLoS Computational Biology, Vol 20, Iss 1, p e

    2024  Volume 1011151

    Abstract: The mammalian cell cycle is regulated by a well-studied but complex biochemical reaction system. Computational models provide a particularly systematic and systemic description of the mechanisms governing mammalian cell cycle control. By combining both ... ...

    Abstract The mammalian cell cycle is regulated by a well-studied but complex biochemical reaction system. Computational models provide a particularly systematic and systemic description of the mechanisms governing mammalian cell cycle control. By combining both state-of-the-art multiplexed experimental methods and powerful computational tools, this work aims at improving on these models along four dimensions: model structure, validation data, validation methodology and model reusability. We developed a comprehensive model structure of the full cell cycle that qualitatively explains the behaviour of human retinal pigment epithelial-1 cells. To estimate the model parameters, time courses of eight cell cycle regulators in two compartments were reconstructed from single cell snapshot measurements. After optimisation with a parallel global optimisation metaheuristic we obtained excellent agreements between simulations and measurements. The PEtab specification of the optimisation problem facilitates reuse of model, data and/or optimisation results. Future perturbation experiments will improve parameter identifiability and allow for testing model predictive power. Such a predictive model may aid in drug discovery for cell cycle-related disorders.
    Keywords Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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