Regulation of TRAIL-Induced Apoptosis by Transcriptional Factors

Abstract

In 1995, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was identified based on its sequence homology to other TNF family members (). Among members of the TNF family, TRAIL shares the highest sequence homology with Fas ligand (FasL, CD95L). However, unlike FasL, TRAIL appears to induce apoptosis of tumor cells but not most normal cells (). To date, five receptors for TRAIL have been cloned: TRAIL-R1 (DR4, Apo2A) (), TRAIL-R2 (DR5, TRICK, Killer) (, , , , , ), TRAIL-R3 (DcR1, TRID, LIT) (, , , ), TRAIL-R4 (DcR2, TRUNDD) (), and osteoprotegerin (OPG) (). Unlike other TRAIL receptors, which bind only to TRAIL, osteoprotegerin also binds to osteoprotegerin ligand (OPGL), TRANCE, and RANK ligand (RANKL). TRAIL-R1 and TRAIL-R2 contain intracellular death domains and induce, via coupling with intracellular adaptor proteins, the proteolytic cleavage of caspase-8 (). Caspase-8 activation initiates the extrinsic and intrinsic apoptotic pathways, resulting in caspase-3 cleavage, which is an irreversible step in a cell’s commitment to apoptosis. Other TRAIL receptors do not generate death signals because TRAIL-R3 does not contain a death domain and is attached to the membrane by a glycolipid anchor (,), whereas the death domain of TRAIL-R4 is not functional () and OPG exists only in a soluble form (). Therefore, TRAIL-R3 and TRAIL-R4 might act as decoy receptors by competing with other TRAIL receptors for TRAIL. The expression pattern of TRAIL receptors on certain cell lines might determine their sensitivity to TRAIL. However, the expression of TRAIL decoy receptors is not always related to a cell’s resistance to TRAIL-induced apoptosis (). Other factors may, therefore, play more decisive roles in determining a cell’s sensitivity to TRAIL. In this review, we will focus on NF-κB and PPAR-γ, two transcription factors that were recently found to play important roles in TRAIL-induced apoptosis.