Bid activation

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. 

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. 

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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. 

XU K and thornalley p j (2001) Signal transduction activated by the cancer chemopreventive isothiocyanates cleavage of BID protein, tyrosine phosphorylation and activation of INK , Br J Cancer, 84 670-73. 

Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2 during p-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9, and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein BclXL was found to be another important event during P-carotene-induced apoptosis, suggesting the presence of an extensive feedback amplification loop in P-carotene-induced apoptosis (Prasad et al., 2006). 

Tirona, R. G., Leake, B. F., Merino, G., Kim, R. B., Polymorphisms in OATP-C identification of multiple allelic variants associated with altered transport activity among European-and African-Americans, J. Bid. Chem. 2001, 276, 35669-35675. 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

Proapoptotic cascade activates Bid, which ohgomerizes Bak or Bax into pores that result in the release of cytochrome c, CellDeath and Differentiation 7 1166-1173. 

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. 

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