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Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT PathwaysSignal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.
Document ID
20100017612
Document Type
Conference Paper
Authors
Carra, Claudio (Universities Space Research Association Houston, TX, United States)
Wang, Minli (Universities Space Research Association Houston, TX, United States)
Huff, Janice L. (Universities Space Research Association Houston, TX, United States)
Hada, Megumi (Universities Space Research Association Houston, TX, United States)
ONeill, Peter (California Univ., Lawrence Berkeley National Lab. Berkeley, CA, United States)
Cucinotta, Francis A. (NASA Johnson Space Center Houston, TX, United States)
Date Acquired
August 24, 2013
Publication Date
January 1, 2010
Subject Category
Life Sciences (General)
Report/Patent Number
JSC-CN-20561
Meeting Information
21st Annual NASA Space Radiation Investigators'' Meeting(Port Jefferson, NY)
Distribution Limits
Public
Copyright
Other