Pulling the Trigger for Apoptosis

Science's STKE  08 May 2007:
Vol. 2007, Issue 385, pp. tw157
DOI: 10.1126/stke.3852007tw157

No signaling system is more important to the cell than the elaborate ones that switch cells from survival mode to the process of cell death or apoptosis. The so-called "death receptor"--known alternatively as CD95, Fas, or APO-1--activates one such apoptosis pathway. To better understand the multiple components that influence the cell’s response to activation of CD95, Lavrik et al. used a combination of mathematical modeling and quantitative experiments to decipher the key factors that produce a cell committed to undergo apoptosis. The authors used a cultured cell line derived from human B lymphoblastoid cells (SKW6.4) to further explore their earlier model, which showed that the cells undergo apoptosis only if subjected to a certain threshold of CD95 activation. The activated receptor forms a complex with multiple other proteins, including procaspase 8 (which, when activated, promotes apoptosis) and also an inhibitor of caspase 8 called c-FLIP. The threshold response might mean that low doses of ligand (the authors use an activating antibody, anti-CD95) activate a small amount of caspase 8 that is insufficient to cause apoptosis or, as predicted in the authors’ mathematical model, no activation of caspase 8 until the appropriate threshold is reached. The authors’ experiments, including quantitative Western blotting to estimate the binding affinities of procaspase 8 and c-FLIP at the receptor complex, confirmed that under conditions of subthreshold stimulation of CD95, the binding affinity of c-FLIP for the receptor complex was higher than that of procaspase 8, leading to a suppression of activation of caspase 8. In fact, under these conditions of subthreshold stimulation, CD-95 actually produced a prosurvival signal through activation of the mitogen-activated protein kinases ERK1 and p38, a signal that apparently predominates over the restrained cell death signal. According to the authors’ model, if CD95 does become sufficiently activated, then enough procaspase 8 accumulates in the receptor complex, and becomes activated, to tip the balance and overcome the survival signal. The authors point out that, to develop appropriate therapeutic strategies for diseases in which apoptosis is a factor, it is essential to understand the detailed molecular mechanisms by which such life and death switches are controlled.

I. N. Lavrik, A. Golks, D. Riess, M. Bentele, R. Eils, P. H. Krammer, Analysis of CD95 threshold signaling: Triggering of CD95 (FAS/APO-1) at low concentrations primarily results in survival signaling. J. Biol. Chem. 282, 13664-13671 (2007). [Abstract] [Full Text]