Death receptors and apoptosis. Deadly signaling and evasive tactics.

The availability of large amounts of sequence data has made it possible to identify death receptors by homology. Because the genome has not been analyzed completely, a few additional members of this family probably will be identified in the next few years. Rapid progress also has been made recently on the signaling mechanisms used by the death receptors. Considerable conservation of the intracellular signaling mechanisms is seen between different receptors suggesting that it is unlikely that new elements will be added to the molecular framework of death receptor signaling. The analysis of signaling mechanisms has exposed the complexity and multiplicity of cellular responses on death receptor activation. It is not surprising, therefore, that understanding the biological function the death receptors lags behind their characterization at the molecular level. In particular, the role of death receptors in many disease states, such as myocardial disease, remains to be elucidated. (38) This complexity in death-receptor function has constrained their potential for pharmacological manipulation. In most cases it is not sufficient to simply activate a specific death receptor. Manipulation of only one of the multiple responses induced by the receptor is desirable. Currently, no solutions to this challenge have been applied. The exception to this conundrum may be TRAIL. Injection of recombinant TRAIL has few side effects in animal studies and combination therapies that use TRAIL as a radiation sensitizer show early promise.