Dataset Information

Yao2008_Rb_E2F_Switch

ABSTRACT: This is the model described in the article: A bistable Rb-E2F switch underlies the restriction point Guang Yao, Tae Jun Lee, Seiichi Mori, Joseph R. Nevins, Lingchong You, Nat Cell Biol 2008 10:476-482; PMID: 18364697 ; DOI: 10.1038/ncb1711 . Abstract: The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that the Rb-E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses. Once turned ON by sufficient serum stimulation, E2F can memorize and maintain this ON state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point. This model reproduces the serum-pulse stimulation-protocol in Figure 3(b). To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novere N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

SUBMITTER: Kieran Smallbone

PROVIDER: BIOMD0000000318 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000318?filename=BIOMD0000000318-biopax2.owl	Owl
	BIOMD0000000318?filename=BIOMD0000000318-biopax3.owl	Owl
	BIOMD0000000318?filename=BIOMD0000000318.m	Other
	BIOMD0000000318?filename=BIOMD0000000318.pdf	Pdf
	BIOMD0000000318?filename=BIOMD0000000318.png	Other

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Publications

A bistable Rb-E2F switch underlies the restriction point.

Yao Guang G Lee Tae Jun TJ Mori Seiichi S Nevins Joseph R JR You Lingchong L

Nature cell biology 20080323 4

The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that ...[more]

PMID: 18364697

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Project description:This model is from the article: Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex. Conradie R, Bruggeman FJ, Ciliberto A, Csikász-Nagy A, Novák B, Westerhoff HV, Snoep JL FEBS J.2010 Jan; 277(2): 357-67 20015233, Abstract: Numerous top-down kinetic models have been constructed to describe the cell cycle. These models have typically been constructed, validated and analyzed using model species (molecular intermediates and proteins) and phenotypic observations, and therefore do not focus on the individual model processes (reaction steps). We have developed a method to: (a) quantify the importance of each of the reaction steps in a kinetic model for the positioning of a switch point [i.e. the restriction point (RP)]; (b) relate this control of reaction steps to their effects on molecular species, using sensitivity and co-control analysis; and thereby (c) go beyond a correlation towards a causal relationship between molecular species and effects. The method is generic and can be applied to responses of any type, but is most useful for the analysis of dynamic and emergent responses such as switch points in the cell cycle. The strength of the analysis is illustrated for an existing mammalian cell cycle model focusing on the RP [Novak B, Tyson J (2004) J Theor Biol230, 563-579]. The reactions in the model with the highest RP control were those involved in: (a) the interplay between retinoblastoma protein and E2F transcription factor; (b) those synthesizing the delayed response genes and cyclin D/Cdk4 in response to growth signals; (c) the E2F-dependent cyclin E/Cdk2 synthesis reaction; as well as (d) p27 formation reactions. Nine of the 23 intermediates were shown to have a good correlation between their concentration control and RP control. Sensitivity and co-control analysis indicated that the strongest control of the RP is mediated via the cyclin E/Cdk2:p27 complex concentration. Any perturbation of the RP could be related to a change in the concentration of this complex; apparent effects of other molecular species were indirect and always worked through cyclin E/Cdk2:p27, indicating a causal relationship between this complex and the positioning of the RP. The rate constants presented in the paper have units [per tenth of an hour] and have been changed here to [per hour] (e.g. k16 = 0.25 not 0.025); for further confirmation of the correctness of this change, see the original model (Novak, J Theor Biol 2004 230:563).