DNA double-strand break repair is attenuated in three-dimensional human lung epithelial cell culture exposed to ionizing radiation
نویسندگان
چکیده
Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFβ) is animportant regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumorformation. Mathematical models of signal transduction pathways can be used to elucidate how signal transductionvaries with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can beconsidered through mechanistic based modeling. We developed a mathematical model of the negative feedbackregulation by Smad7 in TGFβ-Smad signaling and are exploring possible connections to the WNT/β-catenin, andATM/ATF2 signaling pathways. A pathway model of TGFβ-Smad signaling that includes Smad7 kinetics based ondata in the scientific literature is described. Kinetic terms included are TGFβ/Smad transcriptional regulation ofSmad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7negative feedback regulation of the TGFβ receptor through direct binding to the TGFβ receptor complex. Thenegative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which aredescribed mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damageresponses mediated by ATM, and with the WNT pathway and consider the design of experiments to test modeldriven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictionsare described.Cancer/Genomic Instability Posters
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