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Special Communication |

To Die or Not to Die:  An Overview of Apoptosis and Its Role in Disease

Steven W. Hetts
JAMA. 1998;279(4):300-307. doi:10.1001/jama.279.4.300.
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The death of cells in tissues of humans and other multicellular organisms is neither always abnormal nor always detrimental. Although necrosis ensues at the sites of massive cellular injury, most cells in the body die through a more subtle, noninflammatory, energy-dependent form of cell death called apoptosis. The number of cells in tissues is determined by the homeostatic balance between proliferation of new cells and death of senescent cells; the rates of proliferation and apoptosis vary widely from tissue to tissue. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically programmed process that can become deranged when the components of the cellular apoptotic machinery are mutated or present in inappropriate quantities. Dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases: cancer, neurodegeneration, autoimmunity, heart disease, and other disorders. Products of genes involved in the regulation and execution of apoptosis are potentially excellent targets for diagnosis and therapeutic intervention in disease processes, and they offer renewed hope for cures and treatments for a wide array of maladies.

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Figure 1.—The apoptotic program is conserved in evolution. A, Tissue-specific signals activate ced-4, which activates ced-3, leading to cell death. If activated, ced-9 can inhibit apoptosis by inhibiting ced-4's activation of ced-3 (and possibly by directly inhibiting ced-3), as indicated by dashed arrow. B, A wide array of factors commit a mammalian cell to die, but the downstream apoptotic machinery is conserved (worm genes homologous to mammalian apoptotic genes are shown in parentheses). Arrows indicate positive interactions; blunted arrows, negative interactions.
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Figure 2.—Apoptotic signaling pathways. Commitment to death: death ligand FasL binds to death receptor Fas to initiate intracellular signaling; the adaptor protein FADD (Fas-associated death domain protein) binds Fas and also binds to caspase-8 (also known as FLICE, a FADD-like interleukin 1β–converting enzyme). Execution: activation of caspase-8 leads to the activation of other caspases; caspases cleave each other's inactive procaspase precursors into active caspases, amplifying the death signal; active caspases mediate execution by cleaving polyadenosine diphosphate ribose polymerase, nuclear lamins, and other cellular proteins and by activating DNA fragmentation factor. Modulation of apoptotic signaling: in some cell types, cytochrome c is released from mitochondria, allowing activation of apoptotic protease activating factor-1 (Apaf-1), also leading to caspase activation;Bcl-2 family members may promote or suppress apoptosis by interacting with Apaf-1 and/or regulating mitochondrial permeability. Arrows do not necessarily imply direct interactions; homologous Caenorhabditis elegans gene products are shown in gray.
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Figure 3.—Active and passive killing pathways. A, Cytotoxic T cells (Tc cells) kill in 3 ways: Fas ligand (FasL) on the Tc cell binds to Fas on the target cell, inducing apoptosis; Tc cells degranulate, releasing both granzyme B, which enters the target cell and directly activates caspases, and perforins, which can form pores in the target cell membrane, causing osmotic lysis. B, T cells can be killed actively or passively. (1) Peripheral self-tolerance: if the T-cell receptor of a T cell binds avidly to self-peptides presented on a self–MHC I (a class I major histocompatibility complex) on a peripheral cell, the T cell may be induced to express FasL, in addition to Fas, thus allowing self-reactive T cells to kill each other and prevent autoimmunity (B1 has been adapted, with permission, from Nagata23). (2) Death by survival factor withdrawal: if an activated T cell that expresses the interleukin 2 receptor (IL-2R) is deprived of interleukin 2 (IL-2), it will undergo apoptosis because of a default death signal that can be suppressed by antiapoptotic members of the Bcl-2 family.

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