Variability to apoptotic response mediated by functional protein levels

When aptosis is induced in cell populations with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), there is a surprising amount of variation in both how long it takes for cells to die and whether or not they will ever do so. For example, when exposed to 50 nanograms of TRAIL and cycloheximide, some mammary gland cells die within 2-5 hours of exposure (about 30%), some die within 5-10 hours (about 40%), some die within 10-25 hours (about 20%), and some do not die at all within the 25 hour time frame (about 10%). Spencer et al recently found that the rate at which the apoptosis promoting protein BID is truncated into its active form tBID to reach a concentration above a certain threshold level set by another set of proteins (the anti-apoptotic BCL2 protein family) is what accounts for most of this variability. Seems to me like a case of competitive enzyme inhibition. tBID then induces pore-forming proteins (BAX and BAK) to self-assemble in mitochondria, which leads to mitochondrial outer membrane permeabilization, the "point of no return" in this cell death pathway. Cool paper, suggesting that we may be able to enhance our anti-cancer approaches by some sort of genetic technique to alter the protein expression levels of the BCL2 family, and then hit the tumorous cells with the TRAIL, for a more powerful one-two punch.

Reference

Spencer SL, et al. 2009 Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459: 428-432. doi:10.1038/459334a.

Chipuk JE, et al. 2006 Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death and Differentiation 1396-1402. doi:10.1038/sj.cdd.4401963.

Bastiaens P. 2009 Systems biology: When it is time to die. Nature 459: 334-335. doi:10.1038/459334a