The DISC serves as a platform to oligomerise and activate pro-caspases 8 and 10 (Kischkel et al, 2000; Sprick et al, 2000). Active caspases 8 and 10 http://www.selleckchem.com/products/Bosutinib.html are released from the DISC and activate executioner caspases, caspases 3, 6 and 7, committing the cell to death. Active caspases 8 and 10 can also cleave and activate Bid, a BH3-only member of the Bcl-2 protein family. Truncated Bid then activates Bax and Bak to induce mitochondrial outer membrane permeabilisation and cytochrome c release (Eskes et al, 2000; Green and Kroemer, 2004). In the cytosol, cytochrome c binds to the WD40 domains of the adaptor protein, Apaf-1, which initiates the assembly of the heptameric apoptosome complex. Pro-caspase-9 is recruited to the apoptosome and becomes activated (Green, 2000).

Activation of the intrinsic apoptosis pathway in this manner serves to amplify the apoptotic signal and guarantees that the programme is irreversible. In certain cells, which are classified as type I cells, the intrinsic apoptosis pathway is not required to commit the cell to apoptosis upon TRAIL receptor activation; however, in other cells, which are classified as type II cells, this amplification loop is essential. Overexpression of anti-apoptotic Bcl-2 proteins inhibits TRAIL-induced apoptosis in type II cells only (Fulda et al, 2002). Poor activation of pro-caspases 8 and 10 at the DISC is probably one of the major factors that account for the type II phenotype (Scaffidi et al, 1999). By competing with pro-caspase-8 for binding to FADD and inhibiting caspase-8 at the DISC, FLICE-inhibitory protein (c-FLIP) may be a key determinant of the type I vs type II phenotype (Scaffidi et al, 1999; Barnhart et al, 2003).

Despite the high homology between DR4 and DR5 and the identical Entinostat core DISC components recruited to DR4 and DR5, the two receptors are not equally involved in transducing the TRAIL-apoptotic signal (Ichikawa et al, 2001; Ashkenazi, 2002; Kelley et al, 2005; van der Sloot et al, 2006). In the colon cancer cell line, Colo205, we have shown that TRAIL induces apoptosis predominantly through DR5 (van der Sloot et al, 2006). Conversely, in the leukaemia cell lines, ML-1 and EM-2, DR4 is the predominant transducer of apoptosis (van Geelen et al, 2003; MacFarlane et al, 2005). So far, there is no clear explanation for the differential activity of DR4 and DR5. Two reports shed some light to possible, selective regulation of DR4 and DR5. These studies have shown that DcR2 selectively inhibited DR5, but not DR4, through a ligand-dependent or ligand-independent association with DR5 (Clancy et al, 2005; Merino et al, 2006). But what regulates DR4 function, or whether there are intracellular regulators specific to DR4 or DR5, is completely unknown.