Programmed cell death caspases

HBV, hepatitis B HCV, hepatitis C IAP, inhibitor of apoptosis protein DBM, IAP binding motifs INCA, inhibitory CARD NASH, non-alcoholic steatohepatitis PCD, programmed cell death PCI, pan-caspase inhibitor OA, osteoarthritis RA, rheumatoid arthritis Smac, second mitochondria-derived activator of caspases TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. 

The situation with the domain families of the ubiquitin-mediated pathway contrasts with the domain families that function in animal and plant programmed cell death, or apoptosis. As reviewed elsewhere (Ara-vind et al., 1999b), a few domains in eukaryotic apoptotic proteins have prokaryotic homologs, including the cysteine protease family of caspases... 

Regulation of programmed cell death (apoptosis) is not only important in normal cell development and homeostasis [1, 2], but also during the process of carcinogenesis [3], Apoptosis is suppressed in most cancer cells and induction of apoptosis is one cancer treatment strategy [4], There are many processes and factors that can be modulated to induce cancer cell apoptosis, such as regulation of factors involved in cell cycle arrest [5], protein kinase modulation [6], caspase family activation [7], and the balance in expression between Bcl-2 family members [8],... 

Apoptosis or programmed cell death is one of the regulatory mechanisms for the removal of unwanted cells. Apoptosis is induced by the stimulation of several different cell surface receptors in association with caspase activation. Apoptosis of a cell is thus a complicated process and can be assayed by various methods. Among widely used methods, the TUNEL assay is described here. 

The granules contain two types of proteins that result in death. First, compounds that produce holes (pores) in the membrane of the cells these are the proteins, perforin and granulysin. Both insert into the membrane to produce the pores. These were once considered to result in death by lysis (i.e. exchange of ions with extracellular space and entry of water into the cell). However, it is now considered that the role of the pores is to enable enzymes in the granules, known as granzymes, to enter the cell. These granzymes contain proteolytic enzymes. They result in death of the cell by proteolysis but, more importantly, activation of specific proteolytic enzymes, known as caspases. These enzymes initiate reactions that result in programmed cell death , i.e. apoptosis (Chapter 20). 

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

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).

Mariante RM, Guimaraes CA, Linden R, Benchimol M (2003) Hydrogen peroxide induces caspase activation and programmed cell death in the amitochondrial Tritrichomonas foetus. Histochem Cell Biol 120 129-141... 

It is widely assumed in the oncology therapeutic area that paclitaxel is cytotoxic to cancer cells and induces apoptosis, a rapid, programmed cell death associated with the activation of caspases (48) and mediated via the mitotic arrest of cells. 

Grutter, M. G., 2000, Caspases key players in programmed cell death. Curr Opin Struct Biol 10 649-655. 

Tier 3 of oxidative stress involves a cytotoxic response and mitochondrial membrane damage that lead to the activation of caspases that mediate programmed cell death (apoptosis) or necrosis, depending on the severity of oxidative insult. 

Apoptosis is programed cell death and differs from necrosis in that it results in minimal inflammation and release of genetic material. Although necrosis is the predominant process that follows acute ischemia, apoptosis is important after more minor injury, particularly within the ischemic penumbra. Apoptosis is executed by the production, activation and action of caspases, which are protein-cleaving enzymes that dismantle cytoskeleton proteins and enzymes responsible for cellular repair (Zhang et al. 2004). Neurons are particularly susceptible to caspase-mediated cell death after cerebral ischemia, as demonstrated by the reduction in infarct size by caspase inhibitors in experimental models. 

Thon L, et al. Ceramide mediates caspase-independent programmed cell death. FASEB J. 2005 19 1945-1956. 

Another important mechanism for promoting programmed cell death is the binding of ligands to the death receptors, which occurs in the extrinsic pathway (8) (Fig. 1). The death receptors recruit and activate caspase-8, which in turn regulates effector caspase-3 and caspase-7. Caspase-8 processes the Bcl-2 family member Bid, which collaborates with other members of the Bcl-2 family to induce cytochrome c release from the mitochondria and thereby activates the downstream intrinsic pathway (9). 

Inhibitor of apoptosis (lAP) proteins inhibit caspases, which are dimeric cysteine proteases responsible for programmed cell death, or apoptosis. lAPs are multidomain proteins that have multiple BIR domain repeats. One family member, the X-linked lAP (XIAP), has three BIR domains, and uses different BIR domains to inhibit different caspases through disparate mechanisms. 

---