A database of rate constants and related quantities has been assembled by [Nature Biotech. 20 (2002) 370] for intracellular signaling downstream of the epidermal growth factor receptor (EGFR). This information was combined with data on metalloprotease activation [Proc. Natl. Acad. Sci. USA 96 (1999) 6235] to build a model of autocrine signal transduction by cancer cells exposed to ionizing radiation. The model predicts prompt activation of mitogen-activated-protein-kinase (MAPK) pathways in response to a radiation-induced shift in the RasGDP↔RasGTP equilibrium toward more RasGTP. A secondary MAPK activation is predicted due to metalloprotease activity that releases transforming growth factor a (TGFα), an autocrine ligand of EGFR. Model predictions were compared to data by [Mol. Biol. Cell 10 (1999) 2493] on extracellular regulated kinase (ERK) activation following a 2 Gy exposure of carcinoma cells in vitro. Good agreement was obtained with the magnitude of prompt and secondary ERK activation; however, the experimental secondary response was delayed relative to the prompt peak more than predicted by our model.
|Number of pages||13|
|State||Published - Sep 2004|
Bibliographical noteFunding Information:
The authors gratefully acknowledge helpful discussions with Dr. Shvartsman of Princeton University. This research was supported by the Biological and Environmental Research Program of the US Department of Energy under grant number DE-FG03-01ER63234.
- Radiation therapy
- Signalling processes
ASJC Scopus subject areas
- Theoretical Computer Science
- Hardware and Architecture
- Computer Networks and Communications
- Computer Graphics and Computer-Aided Design
- Artificial Intelligence