Truncated BID

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. 

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. 

Apoptosis is caused by the release or activation of one or more BH3 domain-only proteins (Fig. 13.9c, step 1). These initiating B 13-only proteins bind to a cytosolic heterodimer containing a Bcl-2 protein (step 2) and displace a previously bound BH3-only protein, Bid, BIM or PUMA (step 3). In the case of Bid, dissociation from a partner such as Bcl-2 may be mediated by proteolysis of the Bid N-terminal 60 amino acid residues, creating truncated Bid (tBid), which activates an effector protein. The BH3-only proteins are therefore activators of apoptosis that displace effector proteins (BAK or BAX) from a non-Bcl-2 partner on the cytosolic surface of mitochondria and endoplasmic reticulum (step 4). For example, BAK is attached to an outer mitochondrial membrane channel protein in a healthy cell. An activating BH3-only protein displaces BAK, which then self-aggregates into homodimers that burrow a hole in the mitochondrial or endoplasmic reticular membrane, releasing the contents (step 5). 

Fig. 5 Cell death induced by disruption of lysosomes. An endocytic vesicle is ruptured by the photochemical treatment and lysosomal enzymes and the photosensitizer is released into the cytosol. Large quantities of lysosomal enzymes will rapidly degrade vital proteins and cause necrosis, while lower quantities may cleave bid (to form truncated t-bid) and thereby induce apoptosis as indicated on the figure. The photosensitizer will relocate to other organelles during light exposure and induce photodamage to these organelles...

D. S. Middlemas, R. A. Lindberg, and T. Hunter. trkB, a neural receptor protein-tyrosine tdnase evidence for a full-length and two truncated receptors. Mol Cell Bid, 11 (1), 143-153, 1991. 

Depending on the cell type, two different downstream pathways are triggered. In type I cells, processed caspase-8 produced in large amounts directly activates a caspase cascade. Among the caspases activated are caspase-3, which cleaves other caspases or vital substrates of the cell and thus paves the way for the execution phase of apoptosis. In type II cells, proper activation of effector caspases requires amplification via the mitochondrial pathway of apoptosis. Here, smaller amounts of active caspase-3 are produced which cleave the pro-apoptotic Bcl-2 family member Bid. The truncated form of Bid activates mitochondria by an unknown mechanism, which now release pro-apoptotic proteins like cytochrome c and Smac/Diablo (see Section 15.5). Cytochrome c release triggers the formation of the apoptosome, resulting in the activation of caspase-9 and subsequently caspase-3, which in turn can activate caspase-8 outside the Fas-DISC. 

The anchoring effects make it difficult to interpret the answers to the open-ended WTP questions. As a consequence, we will, in the following, focus on the mean WTP estimates ofthe binary choice WTP questions. The anchoring effects also throw doubt on the procedure used above to truncate the binary choice models at 1TL2 500 000, since answers that may have been influenced by the bids are used for the truncation. However, we will... 

The hallmark feature of the Bcl-2 proteins is their ability to form hetero-or homodimers [69-71], The BH domains are the key to this property and form a-helical structures that serve as protein protein interaction motifs. For example, the BH4 domain (found in most, but not all anti-apoptotic family members) may be responsible for molecular interactions with calcineurin and Raf-1 [72, 73], The importance of the BH4 domain is emphasised by the fact that in cells transfected with a mutant or truncated form of Bcl-2 (an anti-apoptotic protein) apoptosis is accelerated [74,75], There is also some evidence that this BH4 domain may be involved in control of the voltage-dependent anion channel of mitochondria [76], Some pro-apoptotic proteins (e.g. Bik, Bid and Bad) only possess the BH3 domain. Consequently, this has led to the idea that this domain is the minimal death domain required for the activity of some pro-apoptotic proteins. 

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