Oct 13, 2015

Population heterogeneity in the epithelial to mesenchymal transition is controlled by NFAT and phosphorylated Sp1

BioRxiv : the Preprint Server for Biology
Russell GouldJonathan Butcher

Abstract

Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble transforming growth factor β (TGF-β) family members, and restricted by vascular endothelial growth factor fam- ily members. While many downstream molecular regulators of EMT have been identified, these have been largely evaluated individually without considering potential crosstalk. In this study, we created an ensemble of dynamic mathematical models describing TGF-β induced EMT to better understand the operational hierarchy of this complex molecular pro- gram. We used ordinary differential equations (ODEs) to describe the transcriptional and post-translational regulatory events driving EMT. Model parameters were estimated from multiple data sets using multiobjective optimization, in combination with cross-validation. TGF-β exposure drove the model population toward a mesenchymal phenotype, while an epithelial phenotype was enhanced following vascular endothelial growth factor A (VEGF- A) exposure. Simulations predicted that the transcription factors phosphorylated SP1 and NFAT were master regulators promoting or inhibiting EMT, respectively. Surprisingly, simulations also pred...Continue Reading

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Mentioned in this Paper

Biological Markers
Recombinant Transforming Growth Factor
Study
Transforming Growth Factor beta
TGFA protein, human
Vascular Endothelial Cells
Transcription, Genetic
VEGFA gene
Vascular Endothelial Growth Factors
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