Death-receptor-triggered Apoptosis

Overall, regulation of caspase activation is little understood, since other protein factors of unknown function are also involved in activation. It can be assumed that there are other apoptotic pathways in addition to the two main pathways described here. In addition, crosstaIk between the pathways may occur. 

Procaspase 8 functions as an initiator caspase in this system, since its activation is the signal for activation of the downstream caspase cascade. The DED motif of caspase 8 is localized in its large prodomain. Similar motives are foimd in other caspases with large prodomains (caspases 2, 8 and 9). 

Upon recruitment by FADD, caspase 8 oligomerizes, triggering activation by selfcleavage. Caspase 8 then proteolytically activates downstream effector caspases, such as caspase 9, and commits the cell to death. 

Binding of the ligand of the Fas receptor triggers clustering of the receptor and association of the cofactor FADD (fas-assodated protein with death domain) which interacts with the receptor via its death domain (DD). Procaspase 8 binds to FADD via a common DED (death effector domain) motif and is thereby also recruited into the Fas-receptor associated complex. Due to the clustering of the proteins, proximity-induced cleavage of procaspase 8 to the mature initiator caspase 8 takes place. This activates the effector caspases and triggers cell death. 

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It is worth mentioning that in death receptor-mediated apoptosis, cells can be divided into two groups depending on the requirement for mitochondria to induce a complete apoptotic response. Type I cells do not require the mitochondrial pathway because the recruitment of procaspase-8 into the DISC complex is enough to fully activate caspase-8 which then activates effector caspases. However, Type II cells are characterized by an incomplete apoptotic response unless mitochondria are involved (Scaffidi et al., 1999). In this type of cell, efficient activation of effector caspases requires the mitochondrial amplification loop (Fig. 5). Caspase-8 cleaves cytosolic Bid, a BH3-only protein, which when cleaved to tBid is able to translocate to the mitochondria and trigger release of the proapoptotic factors cytochrome c and Smac/DIABLO (Li et al., 1998 Deng et al., 2002). The release of cytochrome c triggers apoptosome formation, subsequent caspase-9 activation, and finally the activation of effector caspases such as caspase-3. 

Dirsch VM, Stuppner H, VoUmar AM (2001) Helenalin Triggers a CD95 Death receptor independent apoptosis that is not affected by overexpression of Bcl-xL or Bcl-21. Cancer Res 6 5817... 

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). 

TNF-a is identical to cachetin, a protein that suppresses completely the lipoprotein lipase of adipose tissue and is believed to be responsible for cachexia, a condition of general ill health, malnutrition, weight loss, and wasting of muscle that accompanies cancer and other chronic diseases. Nevertheless, TNF-a may be overproduced in obesity as well. It has been suggested that abnormal production of TNF-a may induce cachexia while abnormal action of the cytokine may cause obesity.233 Some TNF receptors have "death domains" and trigger apoptosis, while other receptors promote proliferation and differentiation via transcription factor NF-kB.242... 

The apoptotic machinery is controlled, like the cell cyde, by internal and external signals. External signals are received by receptors. The receptors that trigger apoptosis are called death receptors. Alfhou they may participate in other cellular signal transduction pathways, when they interact with death ligands they activate death effectors. The effectors are the caspases, a family of C5 teine proteases which eventually destroy the cell. 

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