Control of TRAIL-Induced Apoptosis by a Family of Signaling and Decoy Receptors

Abstract

TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli.

Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line

“…Both recombinant, soluble TRAIL and wild-type, membrane-bound TRAIL induce apoptosis in a wide variety of transformed cell lines via interaction with one or both of the death receptors DR4/TRAIL-R1 and DR5/TRAIL-R2, 12,13 which in turn initiates activation of caspase-8 through FADD, leading to apoptosis. [14][15][16] However, the antagonistic decoy receptors DcR1, 17,18 DcR2, 19 and osteoprotegerin 20 are believed to protect normal cells from the cytotoxic effects of TRAIL by competing with DR4/TRAIL-R1 and DR5/TRAIL-R2 for TRAIL binding.…”

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

“…Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, also called APO-2L is a member of the tumor necrosis factor family that appears to induce apoptosis predominantly in transformed cells (Wiley et al, 1995;Sheridan et al, 1997), but also in some normal cells, for example stimulated splenocytes, memory or dendritic cells (Ursini- Siegel et al, 2002;Hayakawa et al, 2004;Janssen et al, 2005). Tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis by binding to one of the two death domain-containing TRAIL receptors, that is DR4 (TRAIL receptor 1) and DR5 (TRAIL receptor 2) (Sheridan et al, 1997). In contrast to humans, mice do not seem to express a receptor homologous to DR4 and the mouse DR5-homolog seems to be the only death-inducing receptor of TRAIL (Wu et al, 1999).…”

“…In contrast to humans, mice do not seem to express a receptor homologous to DR4 and the mouse DR5-homolog seems to be the only death-inducing receptor of TRAIL (Wu et al, 1999). Tumor necrosis factor-related apoptosis-inducing ligand also binds to the decoy receptors DcR1 (TRAIL-R3) (Sheridan et al, 1997) and DcR2 (TRAIL-R4) , but these receptors contain either no cytoplasmic death domain or a truncated death domain and, therefore, are unable to induce apoptosis. Finally, TRAIL interacts with osteoprotegerin, a secreted soluble protein; however, the functional significance of this interaction is less clear (Emery et al, 1998).…”

True

“…Decoy receptors lack the death domain portion of the molecule, and therefore act as an antagonist to the DR4 and DR5 receptors. 4,[34][35][36][37] In a previous publication we demonstrated that Fas-induced apoptosis is not blocked by overexpression of bcl-2. 30 More recently, we demonstrated that TNF␣-induced apoptosis in myeloma cells is also resistant to bcl-2.…”