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Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments.

ABSTRACT: Cell cycle progression is carefully coordinated with a cell's intra- and extracellular environment. While some pathways have been identified that communicate information from the environment to the cell cycle, a systematic understanding of how this information is dynamically processed is lacking. We address this by performing dynamic sensitivity analysis of three mathematical models of the cell cycle in Saccharomyces cerevisiae. We demonstrate that these models make broadly consistent qualitative predictions about cell cycle progression under dynamically changing conditions. For example, it is shown that the models predict anticorrelated changes in cell size and cell cycle duration under different environments independently of the growth rate. This prediction is validated by comparison to available literature data. Other consistent patterns emerge, such as widespread nonmonotonic changes in cell size down generations in response to parameter changes. We extend our analysis by investigating glucose signalling to the cell cycle, showing that known regulation of Cln3 translation and Cln1,2 transcription by glucose is sufficient to explain the experimentally observed changes in cell cycle dynamics at different glucose concentrations. Together, these results provide a framework for understanding the complex responses the cell cycle is capable of producing in response to dynamic environments.

SUBMITTER: Seaton DD

PROVIDER: S-EPMC4704810 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments.

Seaton Daniel D DD Krishnan J J

PLoS computational biology 20160107 1

Cell cycle progression is carefully coordinated with a cell's intra- and extracellular environment. While some pathways have been identified that communicate information from the environment to the cell cycle, a systematic understanding of how this information is dynamically processed is lacking. We address this by performing dynamic sensitivity analysis of three mathematical models of the cell cycle in Saccharomyces cerevisiae. We demonstrate that these models make broadly consistent qualitativ ...[more]

PMID: 26741131

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Project description:BackgroundThe biochemical oscillator that controls periodic events during the Xenopus embryonic cell cycle is centered on the activity of CDKs, and the cell cycle is driven by a protein circuit that is centered on the cyclin-dependent protein kinase CDK1 and the anaphase-promoting complex (APC). Many studies have been conducted to confirm that the interactions in the cell cycle can produce oscillations and predict behaviors such as synchronization, but much less is known about how the various elaborations and collective behavior of the basic oscillators can affect the robustness of the system. Therefore, in this study, we investigate and model a multi-cell system of the Xenopus embryonic cell cycle oscillators that are coupled through a common complex protein, and then analyze their synchronization ability under four different external stimuli, including a constant input signal, a square-wave periodic signal, a sinusoidal signal and a noise signal.ResultsThrough bifurcation analysis and numerical simulations, we obtain synchronization intervals of the sensitive parameters in the individual oscillator and the coupling parameters in the coupled oscillators. Then, we analyze the effects of these parameters on the synchronization period and amplitude, and find interesting phenomena, e.g., there are two synchronization intervals with activation coefficient in the Hill function of the activated CDK1 that activates the Plk1, and different synchronization intervals have distinct influences on the synchronization period and amplitude. To quantify the speediness and robustness of the synchronization, we use two quantities, the synchronization time and the robustness index, to evaluate the synchronization ability. More interestingly, we find that the coupled system has an optimal signal strength that maximizes the synchronization index under different external stimuli. Simulation results also show that the ability and robustness of the synchronization for the square-wave periodic signal of cyclin synthesis is strongest in comparison to the other three different signals.ConclusionsThese results suggest that the reaction process in which the activated cyclin-CDK1 activates the Plk1 has a very important influence on the synchronization ability of the coupled system, and the square-wave periodic signal of cyclin synthesis is more conducive to the synchronization and robustness of the coupled cell-cycle oscillators. Our study provides insight into the internal mechanisms of the cell cycle system and helps to generate hypotheses for further research.

Project description:Traditional tissue regeneration approaches to activate cell behaviors on biomaterials rely on the use of extracellular-matrix-based or soluble growth-factor cues. In this article, a novel approach is highlighted to dynamically steer cellular phenomena such as cell motility based on nanoscale substratum features of biological ligands. Albumin-derived nanocarriers (ANCs) with variable nanoscale-size features are functionalized with fibronectin III9-10 matrix ligands, and their effects on primary human keratinocyte activation are investigated. The presentation of fibronectin fragments from ANCs significantly enhances cell migration as compared to free ligands at equivalent concentrations. Notably, cell migration is influenced by the size of the underlying ANCs even for variably sized ANCs covered in comparable levels of fibronectin fragment. For equivalent ligand concentrations, cell migration on the smaller-sized ANCs (30 and 50 nm) is significantly enhanced as compared to that on larger-sized ANCs (75 and 100 nm). In contrast, the enhancement of cell migration on nanocarriers is abolished by the use of immobilized, biofunctionalized ANCs, indicating that "dynamic" nanocarrier internalization events underlie the role of nanocarrier geometry on the differential regulation of cell migration kinetics. Uptake studies using fluorescent ANCs indicate that larger-sized ANCs cause delayed endocytic kinetics and hence could present barriers for internalization during the cell adhesion and motility processes. Motile cells exhibit diminished migration upon exposure to clathrin inhibitors, but not caveolin inhibitors, suggesting the role of clathrin-mediated endocytosis in facilitating cell migratory responsiveness to the nanocarriers. Overall, a monotonic relationship is found between the nanocarrier cytointernalization rate and the cell migration rate, suggesting the possibility of designing biointerfacial features for the dynamic control of cell migration. Thus, the functionalization of a mobile nanocarrier by a biorelevant ligand can be used to sensitize cellular motility activation to the adhesion ligands, and such nanocarrier interfaces can dynamically attune cell migration kinetics by modulating the uptake of the ligand-nanocarrier complex via nanocarrier size.

Dataset Information

Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments.

Publications

Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments.

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