Cell death intrinsic pathway

I. Mitochondria -Mediated Cell Death Intrinsic Pathway Apoptosis... 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

C. Both extrinsic and intrinsic pathways can lead to programmed cell death (Figure 14-8). 

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).

Goyeneche AA, Harmon JM, Telleria CM (2006) Cell death induced by serum deprivation in luteal cells involves the intrinsic pathway of apoptosis. Reproduction 131 103-111 Gray MW, Burger G, Lang BF (2001) The origin and early evolution of mitochondria. Genome Biol 2 1018.1-1081.5... 

Increased activity of GSK-3/3 has been reported during neuronal degeneration (Beurel and Jope, 2006) and it has been associated with the promotion of the intrinsic mitochondrial pathway of apoptosis (Brazil and Hemmings, 2001). Pharmacological inhibition of GSK-3/3 reduces neuronal cell death caused by cerebral ischemia (Kelly et al., 2004), suggesting that prevention of GSK-3/3 activation may represent a potential approach to minimize neurodegeneration in the retina. 

Caspase activation occurs as a late and common step in all cells undergoing apoptosis. Nevertheless, there are many initial pathways that can result in caspase activation. Probably, each distinct pathway is triggered by different apoptotic stimuli. In mammalian cells, the apoptotic response is usually mediated by the intrinsic and extrinsic pathways, depending on the origin of the death signal. The intrinsic pathway can further be divided into mitochondrial and ER stress pathways. 

Signaling for apoptosis can be initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway) [31, 32]. In both pathways, signaling results in the activation of initiator caspases. Active initiator caspases then sequentially activate downstream effector caspases such as caspase -3, -6, and -7. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair... 

Mammalian cells contain machinery that permits them to quickly commit apoptosis, or programmed cell death, in response to physiological, pathogenic, or cytotoxic stimuli. Extensive evidence indicates that during apoptosis (intrinsic pathway). 

Figure 1 Schematic representation of the receptor-mediated (extrinsic) and the intracellular stress-mediated (intrinsic) pathways of caspase activation. Death-receptor signaling may involve direct caspase-8-mediated caspase-3 activation (type 1 cells) ora Bid-cleavage-dependent mitochondrial amplification step (type 2 cells).

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). 

During development, programmed cell death is a common norm in developing neurons. However, the intrinsic pro-apoptotic pathways are obliterated as neurons mature. Thus, mere withdrawal of trophic factors does not suffice in inducing their death. Additionally, a genuine apoptotic signal is required for onset of self-suicide process in neurons. Specific gene-products undertake the apoptotic task in different types of neurons and different stimuli may induce distinct apoptotic pathways in them (Pettmann and Henderson, 1998). 

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