Apoptosis pathways

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. 

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

In summary, it appears that the apoptosis pathway can be regulated at various levels (the aforementionned description is far from being exhaustive), while many proteins and cell systems involved in this regulation remain to be discovered. Whereas the cascade of intracellular events implicated in experimentally-induced apoptosis has become more and more elucidated, it is worth noting that only few direct evidences arguing for the presence of an actual apoptosis in the brain of pa-... 

Caspase-4 is down-regulafed and represents a potential block to activation of the apoptosis pathway. 

Severe, life-threatening diseases, such as cancer require a different drug discovery approach. Safety requirements in most oncology targets tolerate more side effects, which otherwise would severely limit the use of a medicine in other indications. For example, in addition to hair loss, a common side effect of cancer treatment, compounds which affect cell cycle, cell proliferation and apoptosis pathways also cause other serious side effects and make the patient endure severe adverse drug reactions (ADRs). 

G8. Greenberg, A. H., Activation of apoptosis pathways by grazyme B. Cell Death Dijfer. 3, 9-16... 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Cells damaged by disease, e.g., dopaminergic neurons in Parkinson disease, may die by apoptosis.147a b A second form of self-destruction occurs when an axon is cut.147b Failure of the elaborate network of mechanism for repair of DNA and maintenance of the genome normally leads to apoptosis. In cancer essential steps in the apoptosis pathway are often inactivated.147c... 

Piwocka K, Jaruga E, Skierski J, Gradzka I, Sikora E. 2001. Effect of glutathione depletion on caspase-3 independent apoptosis pathway induced by curcumin in Jurkat cells. Free Radio Biol Med 31 670-678. 

Interactions between serine proteases are common, and substrates of serine proteases are usually other serine proteases that are activated from an inactive precursor [66]. The involvement of serine proteases in cascade pathways is well documented. One important example is the blood coagulation cascade. Blood clots are formed by a series of zymogen activations. In this enzymatic cascade, the activated form of one factor catalyzes the activation of the next factor. Very small amounts of the initial factors are sufficient to trigger the cascade because of the catalytic nature of the process. These numerous steps yield a large amplification, thus ensuring a rapid and amplified response to trauma. A similar mechanism is involved in the dissolution of blood clots. A third important example of the coordinated action of serine proteases is the intestinal digestive enzymes. The apoptosis pathway is another important example of coordinated action of other types of proteases. 

When AIF and endonuclease G are released into the cytoplasm, they directly translocate to the nucleus and induce DNA fragmentation and subsequent chromosomal condensation, a remarkable morphological feature of the apoptotic process. AIF induces chromatin digestion into large fragments of approximately 50 kb, probably by activating a nuclear DNAse. Therefore, these proteins are important for the caspase-indepen-dent apoptosis pathway. 

Cohen, G. M. Caspases The executioners of apoptosis. Biochem. J. 326(Pt 1), 1-16,1997. Fulda, S., and Debatin, K. M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798-4811, 2006. 

We begin our discourse on cell death with a summary of the tools and the components of the machinery that carry out the CD programme. We shall see that, despite a bewildering variety of new names, regulation of the apoptosis pathways has basic features in common with other cellular signalling pathways. 

D. R. Green. A Myc-induced apoptosis pathway surfaces. Science, 278, 1246-1247, 1997. 

Example 2 Characterization of Apoptosis Pathways Using High-Throughput Image-Based Assays (from Prelux)... 

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