Apoptotic Pathways

Apoptosis is initiated by the activation of one or both of two major pathways. An extrinsic pathway (Fig. 1) is initiated by ligands, such as TNF-a and FasL, which, depending on cell type and circumstances, can result in growth arrest, apoptosis, or cell division (13). Death receptors of the TNF family, such as TNFR1, Fas, and TRAIL, recruit, on binding ligand, molecules that make up a death-inducing complex that includes procaspase 8 (14). This activates caspase 8, which in turn activates caspase 3, but also results in the activation of regulatory pathways, including those mediated by NF-kB , mitogen-activated protein kinases, and c-Jun NH2-terminal kinases (JNKs) (15-17). The activation of these additional pathways explains why TNF-a usually does not cause apoptosis unless an inhibitor of protein synthesis is present. When NF-kB is activated, it becomes a transcription factor for Bcl-2, Bc1-Xl, and various IAPs. Activation of JNK usually causes apoptosis, but in some cell lines, including IEC-6 cells, JNK is inhibited by the activation of MEK1 or ERK 1/2 (18).

The second major pathway is the intrinsic or mitochondrial pathway, which results in the release of cytochrome c from mitochondria and the activation of caspase 9 (Fig. 2). This pathway is regulated by the Bcl-2 family proteins and is usually initiated by DNA damage. Agents such as chemotherapeutic drugs, ultraviolet irradiation, y-irradiation, and reactive oxygen species frequently activate p53, which as a transcription factor leads to the synthesis of proapoptotic members of the Bcl-2 family, such as Bax and

Fig. 1. Extrinsic or death receptor pathway. (See Subheading 2.2. for explanation and discussion.)

Apoptosis

Fig. 1. Extrinsic or death receptor pathway. (See Subheading 2.2. for explanation and discussion.)

Bak. There is also crosstalk between the extrinsic and intrinsic pathways, for caspase 8 cleaves Bid forming the active, truncated ¿-Bid, which can bind Bcl-2 and inactivate it, resulting in apoptosis.

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