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Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways

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Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways : insights from spatio-temporal modelling. / Sturrock, Marc; Terry, Alan J.; Xirodimas, Dimitris P.; Thompson, Alastair M.; Chaplain, Mark A. J.

In: Bulletin of Mathematical Biology, Vol. 74, No. 7, 07.2012, p. 1531-1579.

Research output: Contribution to journalArticle

Harvard

Sturrock, M, Terry, AJ, Xirodimas, DP, Thompson, AM & Chaplain, MAJ 2012, 'Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways: insights from spatio-temporal modelling' Bulletin of Mathematical Biology, vol 74, no. 7, pp. 1531-1579.

APA

Sturrock, M., Terry, A. J., Xirodimas, D. P., Thompson, A. M., & Chaplain, M. A. J. (2012). Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways: insights from spatio-temporal modelling. Bulletin of Mathematical Biology, 74(7), 1531-1579doi: 10.1007/s11538-012-9725-1

Vancouver

Sturrock M, Terry AJ, Xirodimas DP, Thompson AM, Chaplain MAJ. Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways: insights from spatio-temporal modelling. Bulletin of Mathematical Biology. 2012 Jul;74(7):1531-1579.

Author

Sturrock, Marc; Terry, Alan J.; Xirodimas, Dimitris P.; Thompson, Alastair M.; Chaplain, Mark A. J. / Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways : insights from spatio-temporal modelling.

In: Bulletin of Mathematical Biology, Vol. 74, No. 7, 07.2012, p. 1531-1579.

Research output: Contribution to journalArticle

Bibtex - Download

@article{bbbddeb201e8467eab64e698e9f0878c,
title = "Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways",
author = "Marc Sturrock and Terry, {Alan J.} and Xirodimas, {Dimitris P.} and Thompson, {Alastair M.} and Chaplain, {Mark A. J.}",
year = "2012",
volume = "74",
number = "7",
pages = "1531--1579",
journal = "Bulletin of Mathematical Biology",
issn = "0092-8240",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways

T2 - insights from spatio-temporal modelling

A1 - Sturrock,Marc

A1 - Terry,Alan J.

A1 - Xirodimas,Dimitris P.

A1 - Thompson,Alastair M.

A1 - Chaplain,Mark A. J.

AU - Sturrock,Marc

AU - Terry,Alan J.

AU - Xirodimas,Dimitris P.

AU - Thompson,Alastair M.

AU - Chaplain,Mark A. J.

PY - 2012/7

Y1 - 2012/7

N2 - There are many intracellular signalling pathways where the spatial distribution of the molecular species cannot be neglected. These pathways often contain negative feedback loops and can exhibit oscillatory dynamics in space and time. Two such pathways are those involving Hes1 and p53-Mdm2, both of which are implicated in cancer.</p><p>In this paper we further develop the partial differential equation (PDE) models of Sturrock et al. (J. Theor. Biol., 273:15-31, 2011) which were used to study these dynamics. We extend these PDE models by including a nuclear membrane and active transport, assuming that proteins are convected in the cytoplasm towards the nucleus in order to model transport along microtubules. We also account for Mdm2 inhibition of p53 transcriptional activity.</p><p>Through numerical simulations we find ranges of values for the model parameters such that sustained oscillatory dynamics occur, consistent with available experimental measurements. We also find that our model extensions act to broaden the parameter ranges that yield oscillations. Hence oscillatory behaviour is made more robust by the inclusion of both the nuclear membrane and active transport. In order to bridge the gap between in vivo and in silico experiments, we investigate more realistic cell geometries by using an imported image of a real cell as our computational domain. For the extended p53-Mdm2 model, we consider the effect of microtubule-disrupting drugs and proteasome inhibitor drugs, obtaining results that are in agreement with experimental studies.

AB - There are many intracellular signalling pathways where the spatial distribution of the molecular species cannot be neglected. These pathways often contain negative feedback loops and can exhibit oscillatory dynamics in space and time. Two such pathways are those involving Hes1 and p53-Mdm2, both of which are implicated in cancer.</p><p>In this paper we further develop the partial differential equation (PDE) models of Sturrock et al. (J. Theor. Biol., 273:15-31, 2011) which were used to study these dynamics. We extend these PDE models by including a nuclear membrane and active transport, assuming that proteins are convected in the cytoplasm towards the nucleus in order to model transport along microtubules. We also account for Mdm2 inhibition of p53 transcriptional activity.</p><p>Through numerical simulations we find ranges of values for the model parameters such that sustained oscillatory dynamics occur, consistent with available experimental measurements. We also find that our model extensions act to broaden the parameter ranges that yield oscillations. Hence oscillatory behaviour is made more robust by the inclusion of both the nuclear membrane and active transport. In order to bridge the gap between in vivo and in silico experiments, we investigate more realistic cell geometries by using an imported image of a real cell as our computational domain. For the extended p53-Mdm2 model, we consider the effect of microtubule-disrupting drugs and proteasome inhibitor drugs, obtaining results that are in agreement with experimental studies.

U2 - 10.1007/s11538-012-9725-1

DO - 10.1007/s11538-012-9725-1

M1 - Article

JO - Bulletin of Mathematical Biology

JF - Bulletin of Mathematical Biology

SN - 0092-8240

IS - 7

VL - 74

SP - 1531

EP - 1579

ER -

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