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, Bashar

doi:10.1089/omi.2015.0027

Cited by 8 publications

(10 citation statements)

References 71 publications

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“…BubR1 ensures proper separation of chromosomes continuing the process of cell mitosis via monitoring the status of the microtubule gap junction and tension in the centromeres (40). BubR1 is a direct inhibitor of APC (41). There is a dose-dependent effect between the expression level of BubR1 and the function of the SAC (42).…”

Section: A B C D Ementioning

confidence: 99%

Chelidonine induces mitotic slippage and apoptotic-like death in SGC-7901 human gastric carcinoma cells

Zou

Zhang

et al. 2015

Molecular Medicine Reports

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The aim of the present study was to investigate the effect of chelidonine on mitotic slippage and apoptotic-like death in SGC-7901 human gastric cancer cells. The MTT assay was performed to detect the antiproliferative effect of chelidonine. Following treatment with chelidonine (10 µmol/l), the ultrastructure changes in SGC-7901, MCF-7 and HepG2 cells were observed by transmission electron microscopy. The effects of chelidonine on G2/M phase arrest and apoptosis of SGC-7901 cells were determined by flow cytometry. Indirect immunofluorescence assay and laser scanning confocal microscopy (LSCM) were used to detect the phosphorylation level of histone H3 (Ser10) and microtubule formation was detected using LSCM following immunofluorescent labeling. Subsequent to treatment with chelidonine (10 µmol/l), expression levels of mitotic slippage-associated proteins, including BUB1 mitotic checkpoint serine/threonine kinase B (BubR1), cyclin-dependent kinase 1 (Cdk1) and cyclin B1, and apoptosis-associated protein, caspase-3 were examined by western blotting at 24, 48 and 72 h. The half maximal inhibitory concentration of chelidonine was 23.13 µmol/l over 48 h and chelidonine induced G2/M phase arrest of cells. The phosphorylation of histone H3 at Ser10 was significantly increased following treatment with chelidonine for 24 h, indicating that chelidonine arrested the SGC-7901 cells in the M phase. Chelidonine inhibited microtubule polymerization, destroyed microtubule structures and induced cell cycle arrest in the M phase. Giant cells were observed with multiple micronuclei of varying sizes, which indicated that following a prolonged arrest in the M phase, the cells underwent mitotic catastrophe. Western blotting demonstrated that the protein expression levels of BubR1, cyclin B1 and Cdk1 decreased significantly between 48 and 72 h. Low expression levels of BubR1 and inactivation of the cyclin B1-Cdk1 complex results in the cells being arrested at mitosis and leads to mitotic slippage. In addition, apoptotic morphological changes in multinucleated cells were observed, the apoptosis rates increased gradually with administration of chelidonine in a time-dependent manner and the protein levels of caspase-3 increased significantly between 24 and 72 h. Thus, chelidonine induces mitotic slippage, and apoptotic-like death occurs in SGC-7901 cells undergoing mitotic catastrophe. Gastric cancer is a common malignancy, and ranks second in overall cancer-associated mortalities worldwide. The present study demonstrated that chelidonine induces M phase arrest and mitotic slippage of SGC-7901 human gastric carcinoma cells via downregulating the expression of BubR1, Cdk1 and cyclin B1 proteins. With the prolongation of chelidonine treatment, the giant cells with multiple micronuclei underwent mitotic slippage and were maintained in the G1 phase and did not survive. A number of multinucleated cells underwent apoptosis via a caspase-dependent signaling pathway. The current study proposes that chelidonine induces mitotic slippage and apopto...

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Section: A B C D Ementioning

confidence: 99%

Chelidonine induces mitotic slippage and apoptotic-like death in SGC-7901 human gastric carcinoma cells

Zou

Zhang

et al. 2015

Molecular Medicine Reports

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“…The following four model variants are considered: First is the core MCC model which consists of reactions (R1–R5, and R7, see also [20] ). The second variant is the MCC–BubR1 model which consists of reactions (R1–R7, see also [13] ). These model variants serve as the basic and reference models to compare with.…”

Section: Resultsmentioning

confidence: 99%

Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control

Ibrahim

2015

Computational and Structural Biotechnology Journal

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The spindle checkpoint assembly (SAC) ensures genome fidelity by temporarily delaying anaphase onset, until all chromosomes are properly attached to the mitotic spindle. The SAC delays mitotic progression by preventing activation of the ubiquitin ligase anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation marking the transition into anaphase. The mitotic checkpoint complex (MCC), which contains Cdc20 as a subunit, binds stably to the APC/C. Compelling evidence by Izawa and Pines (Nature 2014; 10.1038/nature13911) indicates that the MCC can inhibit a second Cdc20 that has already bound and activated the APC/C. Whether or not MCC per se is sufficient to fully sequester Cdc20 and inhibit APC/C remains unclear. Here, a dynamic model for SAC regulation in which the MCC binds a second Cdc20 was constructed. This model is compared to the MCC, and the MCC-and-BubR1 (dual inhibition of APC) core model variants and subsequently validated with experimental data from the literature. By using ordinary nonlinear differential equations and spatial simulations, it is shown that the SAC works sufficiently to fully sequester Cdc20 and completely inhibit APC/C activity. This study highlights the principle that a systems biology approach is vital for molecular biology and could also be used for creating hypotheses to design future experiments.

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“…The ODE or discrete models generally ignore the topology, while PDEs consider the spatial distribution to some extent (e.g., diffusion but not geometry of molecules). EBM does not deal with single entities but rather with describing populations by estimating the mean behavior at a macroscopic level [3,62,64,69,70,88]. It uses a set of equations that are based on the relationships among observables.…”

Section: Spatial Propertiesmentioning

confidence: 99%

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

Cited by 8 publications

References 71 publications

Chelidonine induces mitotic slippage and apoptotic-like death in SGC-7901 human gastric carcinoma cells

Chelidonine induces mitotic slippage and apoptotic-like death in SGC-7901 human gastric carcinoma cells

Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control

Trends in mathematical modeling of host–pathogen interactions

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