Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions

Rombouts, Jan; Gelens, Lendert

doi:10.1371/journal.pcbi.1008231

Cited by 24 publications

(29 citation statements)

References 103 publications

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“…Interestingly, the bistable nature of the cell cycle transitions itself can provide the means for this regulation by shifting the (in)activation thresholds (i.e. folding points) of the S-shaped response curves to lower or higher levels [ 13 , 70 , 71 ].…”

Section: Resultsmentioning

confidence: 99%

A modular approach for modeling the cell cycle based on functional response curves

2021

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Modeling biochemical reactions by means of differential equations often results in systems with a large number of variables and parameters. As this might complicate the interpretation and generalization of the obtained results, it is often desirable to reduce the complexity of the model. One way to accomplish this is by replacing the detailed reaction mechanisms of certain modules in the model by a mathematical expression that qualitatively describes the dynamical behavior of these modules. Such an approach has been widely adopted for ultrasensitive responses, for which underlying reaction mechanisms are often replaced by a single Hill function. Also time delays are usually accounted for by using an explicit delay in delay differential equations. In contrast, however, S-shaped response curves, which by definition have multiple output values for certain input values and are often encountered in bistable systems, are not easily modeled in such an explicit way. Here, we extend the classical Hill function into a mathematical expression that can be used to describe both ultrasensitive and S-shaped responses. We show how three ubiquitous modules (ultrasensitive responses, S-shaped responses and time delays) can be combined in different configurations and explore the dynamics of these systems. As an example, we apply our strategy to set up a model of the cell cycle consisting of multiple bistable switches, which can incorporate events such as DNA damage and coupling to the circadian clock in a phenomenological way.

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Section: Resultsmentioning

confidence: 99%

A modular approach for modeling the cell cycle based on functional response curves

2021

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“…Mechanistic studies of miR-200-regulated networks have revealed the role of these miRNAs as central hubs of two-node double negative feedback loops (DNFL) in which transcription factors (TF) suppress expression of miR-200 which, in turn, negatively regulate the TF ( Figure 2 ). Interestingly, DNFL generate bi-stable switches that confer robustness and plasticity to critical regulatory circuits which, in response to variation of biological parameters beyond a threshold value, abruptly switch between on- and off-states [ 242 ]. Collected evidence converges over a central position of the miR-200 family in at least 4 DNFL ( Figure 2 ) controlling the EMT-MET switch (ZEB/SNAIL), as well as two pervasive shapers of the cell’s transcriptomic landscape (Myc and SIRT1), which play a key role in the progression towards metastatic dissemination.…”

Section: Discussionmentioning

confidence: 99%

The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers

Cavallari

Ciccarese

Sharova

et al. 2021

Cancers

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The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.

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“…Finally, our results could be expanded by including nuclei in our extract preparations, which could be achieved by supplying demembranated sperm chromatin into Xenopus extracts. Theoretical work suggested that the extra dynamic bistable switch induced by nuclear translocation promotes the robustness of cell-cycle oscillations to noise ( 59 ). How changes in cytoplasmic density affect a system in which nuclei are present is currently unknown and can be a promising avenue for research.…”

Section: Discussionmentioning

confidence: 99%

In vitro cell cycle oscillations exhibit a robust and hysteretic response to changes in cytoplasmic density

Jin

Tavella

Wang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Cells control the properties of the cytoplasm to ensure proper functioning of biochemical processes. Recent studies showed that cytoplasmic density varies in both physiological and pathological states of cells undergoing growth, division, differentiation, apoptosis, senescence, and metabolic starvation. Little is known about how cellular processes cope with these cytoplasmic variations. Here, we study how a cell cycle oscillator comprising cyclin-dependent kinase (Cdk1) responds to changes in cytoplasmic density by systematically diluting or concentrating cycling Xenopus egg extracts in cell-like microfluidic droplets. We found that the cell cycle maintains robust oscillations over a wide range of deviations from the endogenous density: as low as 0.2× to more than 1.22× relative cytoplasmic density (RCD). A further dilution or concentration from these values arrested the system in a low or high steady state of Cdk1 activity, respectively. Interestingly, diluting an arrested cytoplasm of 1.22× RCD recovers oscillations at lower than 1× RCD. Thus, the cell cycle switches reversibly between oscillatory and stable steady states at distinct thresholds depending on the direction of tuning, forming a hysteresis loop. We propose a mathematical model which recapitulates these observations and predicts that the Cdk1/Wee1/Cdc25 positive feedback loops do not contribute to the observed robustness, supported by experiments. Our system can be applied to study how cytoplasmic density affects other cellular processes.

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Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions

Cited by 24 publications

References 103 publications

A modular approach for modeling the cell cycle based on functional response curves

A modular approach for modeling the cell cycle based on functional response curves

The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers

In vitro cell cycle oscillations exhibit a robust and hysteretic response to changes in cytoplasmic density

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