Mad2 binding is not sufficient for complete Cdc20 sequestering in mitotic transition control (an in silico study)

Ibrahim, Bashar; Dittrich, Peter; Diekmann, Stephan; Schmitt, Eberhard

doi:10.1016/j.bpc.2008.01.007

Cited by 29 publications

(50 citation statements)

References 35 publications

(86 reference statements)

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“…So far, mathematical models have helped to elucidate the kinetochore structure and with that the mitotic checkpoint mechanism (Doncic et al, 2005;Görlich et al, 2014;Ibrahim et al, 2007;2008b;Ibrahim and Henze, 2014;Kreyssig et al, 2012;Lohel et al, 2009;Sear and Howard, 2006;Simonetta et al, 2009;Tschernyschkow et al, 2013). However, none of these models consider the APC regulatory pathways.…”

Section: Resultsmentioning

confidence: 99%

“…2 · 10 -2 s -1 (Ibrahim et al 2008b, Ibrahim andHenze, 2014) ( Eytan et al 2008), this study Other species start from zero 296 IBRAHIM theoretical point of view (Ibrahim et al, 2008b).This loop was therefore not considered in the model. For integrity, the biochemical equations of the autocatalytic amplification are listed by reaction (R4)-(R5) (see chemical reaction scheme, below).…”

Section: Autocatalytic Amplification Of Cdc20:c-mad2 Formationmentioning

confidence: 99%

“…In this model, if the kinetochore is unattached, u was set to u = 1, otherwise u = 0. Note that it is assumed that mass-action kinetics are used for all reactions (Ibrahim et al, 2008a;2008b). If other kinetics should be used, they have to be transformed to mass action kinetics.…”

Section: Model Assumptionsmentioning

confidence: 99%

“…Mad2-activation at the kinetochores is commonly seen as the central element of the SAC. Therefore the template model of Mad2-activation is included into the model (De Antoni et al, 2005;Ibrahim et al, 2008b;Simonetta et al, 2009). The kinetic rate coefficients for this interactions have been determined in vitro by Simonetta et al (2009).…”

Section: Template Model Of Mad2-activationmentioning

confidence: 99%

“…They found that a diffusible signal can generally account for checkpoint operation. A more comprehensive model of the human SAC, including the Mad2 and BubR1 pathway, has been proposed by Ibrahim et al (2008a;2008b, 2009Ibrahim and Henze, 2014). A mathematical model for checkpoint activation based on the ''Mad2 template'' model by De Antoni et al (2005) is supported with in vitro experiments by Simonetta et al (2009).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Ibrahim

2015

OMICS: A Journal of Integrative Biology

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Correct DNA segregation is a fundamental process that ensures the precise and reliable inheritance of genomic information for the propagation of cell life. Eukaryotic cells have evolved a conserved surveillance control mechanism for DNA segregation named the Spindle Assembly Checkpoint (SAC).The SAC ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome whose activation by Cdc20 is required for sister-chromatid separation; this marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. However, the underlying regulatory pathways remain largely elusive. In this study, five possible model variants of APC/C regulation were constructed, namely BubR1, Mad2, MCC, MCF2, and an all-pathways model variant. These models were validated with experimental data from the literature. A wide range of parameter values has been tested to find the critical values of the APC/C binding rate. The results show that all variants are able to capture the wild-type behavior of the APC/C. However, only one model variant, which included both MCC as well as BubR1 as potent inhibitors of the APC/C, was able to reproduce both wild-type and mutant type behavior of APC/C regulation. In conclusion, the presented work informs the regulation of fundamental processes such as SAC and APC/C in cell biology and has successfully distinguished between five competing dynamical models using a systems biology approach. The results attest that systems-level approaches are vital for molecular and cell biology.

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Section: Resultsmentioning

confidence: 99%

Section: Autocatalytic Amplification Of Cdc20:c-mad2 Formationmentioning

confidence: 99%

Section: Model Assumptionsmentioning

confidence: 99%

Section: Template Model Of Mad2-activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Ibrahim

2015

OMICS: A Journal of Integrative Biology

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Trends in mathematical modeling of host–pathogen interactions

Ewald

Sieber

Garde

et al. 2019

Cell. Mol. Life Sci.

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Pathogenic microorganisms entail enormous problems for humans, livestock, and crop plants. A better understanding of the different infection strategies of the pathogens enables us to derive optimal treatments to mitigate infectious diseases or develop vaccinations preventing the occurrence of infections altogether. In this review, we highlight the current trends in mathematical modeling approaches and related methods used for understanding host-pathogen interactions. Since these interactions can be described on vastly different temporal and spatial scales as well as abstraction levels, a variety of computational and mathematical approaches are presented. Particular emphasis is placed on dynamic optimization, game theory, and spatial modeling, as they are attracting more and more interest in systems biology. Furthermore, these approaches are often combined to illuminate the complexities of the interactions between pathogens and their host. We also discuss the phenomena of molecular mimicry and crypsis as well as the interplay between defense and counter defense. As a conclusion, we provide an overview of method characteristics to assist non-experts in their decision for modeling approaches and interdisciplinary understanding.

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A Mathematical Framework for Kinetochore-Driven Activation Feedback in the Mitotic Checkpoint

Ibrahim

2017

Bull Math Biol

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Proliferating cells properly divide into their daughter cells through a process that is mediated by kinetochores, protein-complexes that assemble at the centromere of each sister chromatid. Each kinetochore has to establish a tight bipolar attachment to the spindle apparatus before sister chromatid separation is initiated. The spindle assembly checkpoint (SAC) links the biophysical attachment status of the kinetochores to mitotic progression and ensures that even a single misaligned kinetochore keeps the checkpoint active. The mechanism by which this is achieved is still elusive. Current computational models of the human SAC disregard important biochemical properties by omitting any kind of feedback loop, proper kinetochore signals, and other spatial properties such as the stability of the system and diffusion effects. To allow for more realistic in silico study of the dynamics of the SAC model, a minimal mathematical framework for SAC activation and silencing is introduced. A nonlinear ordinary differential equation model successfully reproduces bifurcation signaling switches with attachment of all 92 kinetochores and activation of APC/C by kinetochore-driven feedback. A partial differential equation model and mathematical linear stability analyses indicate the influence of diffusion and system stability. The conclusion is that quantitative models of the human SAC should account for the positive feedback on APC/C activation driven by the kinetochores which is essential for SAC silencing. Experimental diffusion coefficients for MCC subcomplexes are found to be insufficient for rapid APC/C inhibition. The presented analysis allows for systems-level understanding of mitotic control, and the minimal new model can function as a basis for developing further quantitative-integrative models of the cell division cycle.

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Mad2 binding is not sufficient for complete Cdc20 sequestering in mitotic transition control (an in silico study)

Cited by 29 publications

References 35 publications

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Trends in mathematical modeling of host–pathogen interactions

A Mathematical Framework for Kinetochore-Driven Activation Feedback in the Mitotic Checkpoint

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