Introduction

Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)


Programmed cell death (also known as PCD) is generally defined as a regulated process by which cells contribute to their own demise. Apoptosis is the best-characterized form of programmed cell death, but alternative non-apoptotic cell-death pathways important in human physiology and disease pathology are now actively studied. Regarding apoptosis, there are two general pathways, the extrinsic pathways and the intrinsic pathways, depending on whether the molecular factor that initiates the death pathway is extra-cellular or intra-cellular. Both extrinsic and intrinsic pathways lead to activation of caspases, the proteases that cleave many key protein targets inside cells, resulting in apoptotic cell morphology and cell death within a few minutes to hours. Although there may be alternative molecular pathways that cause apoptosis-like cell morphology, the term apoptosis most often refers to caspase-dependent cell death.

The extrinsic and intrinsic pathways activate different initiator caspases. Each initiator caspase is activated by a unique complex of proteins. The intrinsic death pathway involves mitochondria and is controlled by pro and anti-apoptotic Bcl-2-family proteins that facilitate or inhibit the release of cytochrome c from the mitochondrial inter-membrane space. In turn, cytosolic cytochrome c and ATP/ADP bind Apaf-1, inducing oligomerization of Apaf-1 into a heptameric ring structure known as the apoptosome. The apoptosome activates caspase-9, which in turn cleaves and activates caspases-3 and -7 to mediate apoptosis during normal development and to prevent cancer. Other intrinsic apoptotic pathways are initiated by assembly of alternative caspase-activating complexes in response to intra-cellular factors, such as the PIDDosome complex, which activates caspase-2, and the inflammasome, which activates caspase-1 (originally known as ICE, IL-1 -converting enzyme).

The extrinsic apoptosis death pathway, the focus of this chapter, also leads to caspase-3 activation when extra-cellular ligands bind and activate receptors expressed on the surface of cells that are destined to die. These cell-surface receptors, known as death receptors, signal through their cytoplasmic tails to assemble various adaptor proteins leading to protein complexes that activate caspases-8 and -10. In turn, caspases-8 and -10 cleave and activate caspases-3 and -7 to cause apoptosis, for example during immune responses. Death receptors can signal both apoptotic and necrotic cell death, as well as cell-survival pathways. The decision points that determine which of these pathways will be fulfilled depends on the specific cell-surface receptor and the composition of the signaling complex that is assembled on their cytoplasmic domains.

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