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Apoptosis is a term originally coined by Wyllie, Kerr, and Currie to describe a form of cell death characterized by cell shrinkage and nuclear condensation, and is derived from the Greek term for the shedding of leaves or petals. This physiologic, tightly regulated process is initiated by eukaryotic cells in response to internal or external cues. Apoptosis occurs in all multicellular organisms as the means to balance cell proliferation in continuously renewing tissues in order to maintain a constant organ size, and to eliminate cells that are unneeded, or defective. In the hematopoietic system, cell production is delicately balanced against cell death and removal through the monocyte–macrophage system. A panoply of cytokines and growth factors regulate cell survival, proliferation, and apoptosis. Stem cell factor, Flt ligand, erythropoietin, thrombopoietin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, IL-5, IL-6, IL-7, and IL-11, amongst others, variably suppress apoptosis and stimulate cell cycling. Tumor necrosis factor-α, Fas ligand, tumor necrosis factor-related apoptosis-inducing ligand, and interferon-γ promote apoptosis of cells expressing the appropriate receptors. Failure of apoptosis leads to tumorigenesis, and many oncogenes and tumor suppressors regulate apoptosis, including p53 and c-myc.

Acronyms and Abbreviations

Abbreviations and acronyms that appear in this chapter include: AML: acute myelogenous leukemia; Apaf-1, apoptotic peptidase-activating factor 1; Bak, Bcl-2 homologous antagonist killer; Bax, Bcl-2–associated X protein; B-CLL, B-cell chronic lymphocytic leukemia; Bcl, B-cell lymphoma; BH, Bcl-2 homology; Bid, BH3 interacting domain death agonist; ced, Caenorhabditis elegans death; CML, chronic myelogenous leukemia; CrmA, cowpox response-modifier protein A; FADD, Fas-associated death domain; IAP, inhibitor of apoptosis protein; ICE, interleukin-1β–converting enzyme; IL, interleukin; TNF, tumor necrosis factor.

Apoptosis, a term coined by Wyllie, Kerr, and Currie,1 occurs at defined times and locations during development, thus earning it the name programmed cell death.2 It is a critical process during embryogenesis, where tissue remodeling requires highly regulated cell death. For example, programmed cell death takes place during the elimination of interdigital webs in mammalian development, and in the regression of the tadpole’s tail as it develops into a frog. Three of the most important genes that control apoptosis were first identified through detailed studies of development in the nematode Caenorhabditis elegans. Two of them, designated C. elegans death (ced)-3 and ced-4, are essential for programmed cell death to occur, and one gene, ced-9, is essential for opposing cell death.3,4 These genes were subsequently found to be conserved throughout evolution and are represented by large families of mammalian homologues. Ced-3 is a cysteine protease with the unusual characteristic of cleaving peptides after aspartic acid residues. The first mammalian homologue of Ced-3 to be identified was interleukin-1β–converting enzyme (ICE). Subsequently, a family of more than 10 related cysteine proteases (“death proteases”) was identified; they are designated caspases, for cysteine aspartases.5 The nematode death gene, ced-4, encodes a protein that controls the activation of the ...

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