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dc.contributor.authorSturrock, Marc
dc.contributor.authorHellander, Andreas
dc.contributor.authorAldakheel, Sahar
dc.contributor.authorPetzold, Linda
dc.contributor.authorChaplain, Mark A. J.
dc.identifier.citationSturrock , M , Hellander , A , Aldakheel , S , Petzold , L & Chaplain , M A J 2014 , ' The role of dimerisation and nuclear transport in the Hes1 gene regulatory network ' , Bulletin of Mathematical Biology , vol. 76 , no. 4 , pp. 766-798 .
dc.identifier.otherRIS: urn:B2A740A77C03E383290B8BB4F4FD7382
dc.identifier.otherORCID: /0000-0001-5727-2160/work/55379011
dc.description.abstractHes1 is a member of the family of basic helix-loop-helix transcription factors and the Hes1 gene regulatory network (GRN) may be described as the canonical example of transcriptional control in eukaryotic cells, since it involves only the Hes1 protein and its own mRNA. Recently, the Hes1 protein has been established as an excellent target for an anti-cancer drug treatment, with the design of a small molecule Hes1 dimerisation inhibitor representing a promising if challenging approach to therapy. In this paper, we extend a previous spatial stochastic model of the Hes1 GRN to include nuclear transport and dimerisation of Hes1 monomers. Initially, we assume that dimerisation occurs only in the cytoplasm, with only dimers being imported into the nucleus. Stochastic simulations of this novel model using the URDME software show that oscillatory dynamics in agreement with experimental studies are retained. Furthermore, we find that our model is robust to changes in the nuclear transport and dimerisation parameters. However, since the precise dynamics of the nuclear import of Hes1 and the localisation of the dimerisation reaction are not known, we consider a second modelling scenario in which we allow for both Hes1 monomers and dimers to be imported into the nucleus, and we allow dimerisation of Hes1 to occur everywhere in the cell. Once again, computational solutions of this second model produce oscillatory dynamics in agreement with experimental studies. We also explore sensitivity of the numerical solutions to nuclear transport and dimerisation parameters. Finally, we compare and contrast the two different modelling scenarios using numerical experiments that simulate dimer disruption, and suggest a biological experiment that could distinguish which model more faithfully captures the Hes1 GRN.
dc.relation.ispartofBulletin of Mathematical Biologyen
dc.subjectSpatial stochastic modellingen
dc.subjectNuclear transporten
dc.subjectQH301 Biologyen
dc.subjectQA Mathematicsen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.titleThe role of dimerisation and nuclear transport in the Hes1 gene regulatory networken
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. Applied Mathematicsen
dc.description.statusPeer revieweden

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