Origin of bistability underlying mammalian cell cycle entry

Yao, Guang; Tan, Cheemeng; West, Mike; Nevins, Joseph R.; Li, You

doi:10.1038/msb.2011.19

Cited by 112 publications

(167 citation statements)

References 56 publications

(75 reference statements)

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“…As in other fields of engineering, advances have been enabled by the use of small interchangeable modules that are 'functionally equivalent' from an input -output perspective [2]. Bistable circuits-which play a role in essential biological processes, including cell fate specification [3], cell cycle progression [4] and apoptosis [5]-make up a particularly large and diverse functionally equivalent set [6]. Effectively characterizing and comparing these biocircuits is crucial for determining which design is in some sense optimal for a particular context.…”

Section: Introductionmentioning

confidence: 99%

An analytical approach to bistable biological circuit discrimination using real algebraic geometry

Siegal-Gaskins

Franco

Zhou

et al. 2015

J. R. Soc. Interface.

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Biomolecular circuits with two distinct and stable steady states have been identified as essential components in a wide range of biological networks, with a variety of mechanisms and topologies giving rise to their important bistable property. Understanding the differences between circuit implementations is an important question, particularly for the synthetic biologist faced with determining which bistable circuit design out of many is best for their specific application. In this work we explore the applicability of Sturm's theorem-a tool from nineteenth-century real algebraic geometryto comparing 'functionally equivalent' bistable circuits without the need for numerical simulation. We first consider two genetic toggle variants and two different positive feedback circuits, and show how specific topological properties present in each type of circuit can serve to increase the size of the regions of parameter space in which they function as switches. We then demonstrate that a single competitive monomeric activator added to a purely monomeric (and otherwise monostable) mutual repressor circuit is sufficient for bistability. Finally, we compare our approach with the Routh-Hurwitz method and derive consistent, yet more powerful, parametric conditions. The predictive power and ease of use of Sturm's theorem demonstrated in this work suggest that algebraic geometric techniques may be underused in biomolecular circuit analysis.

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Section: Introductionmentioning

confidence: 99%

An analytical approach to bistable biological circuit discrimination using real algebraic geometry

Siegal-Gaskins

Franco

Zhou

et al. 2015

J. R. Soc. Interface.

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“…When stochastic gene expression leads to fluctuations in factors involved in positive or double-negative feedback regulation, distinct cellular states within a population can arise (1,(14)(15)(16)(17)(18). Because of the role of p21 in the doublenegative feedback regulation of cell cycle activity, we hypothesized that p21 controlled population heterogeneity in quiescent and cycling cell states.…”

mentioning

confidence: 99%

Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states

Overton¹,

Spencer

Noderer³

et al. 2014

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

101

134

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Phenotypic heterogeneity within a population of genetically identical cells is emerging as a common theme in multiple biological systems, including human cell biology and cancer. Using live-cell imaging, flow cytometry, and kinetic modeling, we showed that two states-quiescence and cell cycling-can coexist within an isogenic population of human cells and resulted from low basal expression levels of p21, a Cyclin-dependent kinase (CDK) inhibitor (CKI). We attribute the p21-dependent heterogeneity in cell cycle activity to double-negative feedback regulation involving CDK2, p21, and E3 ubiquitin ligases. In support of this mechanism, analysis of cells at a point before cell cycle entry (i.e., before the G1/S transition) revealed a p21-CDK2 axis that determines quiescent and cycling cell states. Our findings suggest a mechanistic role for p21 in generating heterogeneity in both normal tissues and tumors.tumor heterogeneity | cell dormancy | synthetic uORF | nongenetic cell heterogeneity | positive feedback loop

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“…This is the property of coexistence of two or more stable steady states [1]. Bistability is very important property in biology which has been implicated in pathology [2]. Therefore understanding the mathematics of bistability is important and there is a gap in the literature because it mainly studies closed systems.…”

Section: Introductionmentioning

confidence: 99%

A structurally unstable bistable system

Siam¹,

Grinfeld

2016

AIP Conference Proceedings

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Abstract. Bistability (or more generally multistability, the coexistence of two or more stable steady states in a dynamical system) is an important property of many dynamical systems in biology. It furnishes an explanation for the ability of isogenic cells to present different stable expression profiles. In this work, we show analytically that the Cdc2-cyclin B/Wee1 system which exhibits bistability when all the protein species are conserved, is not structurally stable when degradation and synthesis of one of the components are taken into account.

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Origin of bistability underlying mammalian cell cycle entry

Abstract: Mammalian cell cycle entry is controlled at the restriction point by a bistable and resettable switch, which is shown to emerge from a minimal gene circuit containing a mutual-inhibition feedback loop between Rb and E2F modules, coupled with a feed-forward loop between Myc and E2F modules.

Cited by 112 publications

References 56 publications

An analytical approach to bistable biological circuit discrimination using real algebraic geometry

An analytical approach to bistable biological circuit discrimination using real algebraic geometry

Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states

A structurally unstable bistable system

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