Origins of cell-to-cell variability in apoptosis

[摘要] (cont.) This dependency was indicated by observation of the height of the MOMP threshold in surviving and dying cells and by modulation of this threshold via overexpression of anti-apoptotic regulators of MOMP. Simulations of cell-to-cell variability in TRAIL-induced apoptosis confirmed that the endogenous variability in apoptotic regulators was sufficient to produce the observed variability in death time. However, knowledge of the concentration of individual proteins did not allow prediction of death time because variation in other proteins masked the underlying trends. The ability to simulate heterogeneity in cellular response also led to the development of novel, biologically intuitive methods of sensitivity analysis, which revealed that sensitivities shift depending on whether knowledge of covariance in initial conditions is included. The ability to predict sensitivity and resistance of tumors to TRAIL would be clinically valuable, as TRAIL is currently in clinical trials as an anti-cancer therapy. The results described here represent progress toward understanding the ;;fractional killing;; of tumor cells following exposure to chemotherapy, and for understanding variability in mammalian signaling pathways in general.

[发布机构] Massachusetts Institute of Technology