Receptor death

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

Wajant H, Gerspach J, Pfizenmaier K (2005) Tumor therapeutics by design targeting and activation of death receptors. Cytokine Growth Factor Rev 16 55-76... 

Death Domain and Death Receptors Death Domain Superfamily Defensins... 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Topo inhibitors are found to be the most efficient inducers of apoptosis. The main pathways leading from topo-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by pro-apoptotic molecules released from mitochondria. In some cells, the apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement of these apoptotic ef-... 

Horinaka M, Yoshida T, Shiraishi T, et al. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene 2005 24 7180-7189. 

Figure 10.5 The death receptor pathway for DNA damage. Reprinted with permission from Hengartner, 2000. Copyright (2000) Macmillan Magazines Limited.

Gulbins, E. Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol. Res. 47 393-399,2003. 

Death receptor activation. Several different ligands can induce apoptosis of neural cells including certain cytokines... 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Szegezdi, E., S. Cahill, M. Meyer, M. O Dwyer, and A. Samali. 2006. TRAIL sensitisation by arsenic trioxide is caspase-8 dependent and involves modulation of death receptor components and Akt. Br J Cancer 94(3) 398 106. 

Antonsson and Marinou 2000 Adams and Cory, 1998). Stress may also cause inaease, nitric oxide (NO), or reactive oxygen species (ROS) production which, in turn, triggers release of apoptotic proteins from the intermemhrane space (Kroemer and Reed, 2000 Vieira et at, 2000). Release of these proteins from mitochondria are required for stress induced killing hut are, with a few exceptions (Bergmann et al, 1994, Schulze- Osthoff et al, 1993), dispensible for CD95 and TNF-receptor transduced apoptosis. These other death processes require FADD and caspase-8 to be recruited into the death receptor complexes and cannot be blocked by Bcl-2 (Krammer, 2000 Scaffidi et al, 1998). 

A link between the pathways controlled by the TNF-receptor family members and the mitochondrial pathway has been identified. It has been shown that caspase-8 can cleave Bid, resulting in the formation of truncated Bid (tBid), a death-inducing member of the Bcl-2 family (Gross et al, 1999 Li et al, 1998 Luo et al., 1998). Bid activation appears not to be essential in cells with high amoimts of caspase-8 in the death receptor complex but may be required to amplify the cascade in cells with low amounts of caspase-8 in the death receptor complex. 

Luo, X., Budihardjo, L, Zou, H., Slaughter, C., and Wang, X., 1998, Bid, a Bcl-2 interacting protein, mediates cythochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94 481-490. 

---