On the TRAIL to apoptosis.

Apoptosis in mammalian cells can be initiated through two major interrelated pathways, one involving engagement of the TNF family of death receptors, the other involving the release of cytochrome c from mitochondria. Unlike other members of the TNF ligand family, TNF-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cell lines, but not in normal cells, suggesting that TRAIL could potentially represent a powerful cancer therapeutic. Recent experiments have revealed that one of the key regulators of TRAIL expression in lymphocytes is the NF-kappa B transcription factors. Several TRAIL receptors have been identified: two of these receptors TRAIL-R1/DR4 and TRAIL-R2/DR5 contain cytoplasmic death domains and signal apoptosis, while two other decoy receptors, TRAIL-R3/DcR1 and TRAIL-R4/DcR2 lack a functional death domain and do not mediate apoptosis. Many cancer cell lines preferentially express TRAIL-R1 and TRAIL-R2, suggesting differential regulation of the death and decoy receptors. Further knowledge of the regulation and physiological role of TRAIL and TRAIL receptors may aid in the rational design of regimens that utilize the TRAIL signaling pathway to eliminate tumor cells.