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Unformatted text preview: chondrial pathway of apoptosis In mammalian cells, many cell death signals induce apoptosis as a result of damage to mitochondria (the intrinsic pathway of apoptosis). When active, the proapoptotic multidomain Bcl-2 family proteins (Bak and Bax) form oligomers in the outer membrane of mitochondria, resulting in the release of cytochrome c from the intermembrane space. Release of cytochrome c leads to the formation of apoptosomes containing Apaf-1 and caspase-9 in which caspase-9 is activated. Caspase-9 then activates downstream caspases, such as caspase-3, by proteolytic cleavage. Death signal Bax chondria by Bax or Bak results not only in the release of cytochrome c but also of IAP inhibitors that may help to stimulate caspase activity. Signaling Pathways that Regulate Apoptosis
Programmed cell death is regulated by the integrated activity of a variety of signaling pathways, some acting to induce cell death and others acting to promote cell survival. These signals control the fate of individual cells, so that cell survival or elimination is determined by the needs of the organism as a whole. The pathways that induce apoptosis in mammalian cells are grouped as intrinisic or extrinsic pathways, which differ in their involvement of Bcl-2 family proteins and in the identity of the caspase that initates cell death. One important role of apoptosis is the elimination of damaged cells, so apoptosis is stimulated by many forms of cell stress, including DNA damage, viral infection, and growth factor deprivation. These stimuli activate the intrinsic pathway of apoptosis, which leads to release of cytochrome c from mitochondria and activation of caspase-9 (see Figure 17.8). As illustrated in the following examples, the multiple signals that activate this pathway converge on regulation of the BH3-only members of the Bcl-2 family. DNA damage is a particularly dangerous form of cell stress, because cells with damaged genomes may have suffered mutations that can lead to the development of cancer. DNA damage is thus one of the principal triggers of programmed cell death, leading to the elimination of cells carrying potentially harmful mutations. As discussed in Chapter 16, several cell cycle checkpoints halt cell cycle progression in response to damaged DNA, allowing time for the damage to be repaired. In mammalian cells, a major pathway leading to cell cycle arrest in response to DNA damage is mediated by the transcription factor p53. The ATM and Chk2 protein kinases, which are activated by DNA damage, phosphorylate and stabilize p53. The resulting increase in p53 leads to transcriptional activation of p53 target genes. These include the Cdk inhibitor p21, which inhibits Cdk2/cyclin E complexes, halting cell cycle progression in G1 (see Figure 16.20). However, activation of p53 by DNA damage can also lead to apoptosis (Figure 17.10). The induction of apoptosis by p53 results, at least in part, from transcriptional activation of genes encoding the BH3-only proapoptotic Bcl-2 family members PUMA and Noxa. Increased expression of these BH3-only proteins leads to activation of Bax and Bak, release of cytochrome c from mitochondria, and activation of caspase-9. Thus p53 mediates both cell cycle arrest and apoptosis in response to DNA damage. Whether DNA damage in a given cell leads to apoptosis or reversible cell cycle arrest may depend on the extent of damage and the resulting level of p53 induction, as well as the influence of other life/death signals being received by the cell. Growth factor deprivation is another form of cell stress that activates the intrinsic pathway of apoptosis. In this case, apoptosis is controlled by signaling pathways that promote cell survival by inhibiting apoptosis in Bax Cytochrome c Apaf-1 Apoptosome Caspase-9 Pro-caspase-3 Active caspase-3 Apoptosis This material cannot be copied, reproduced, manufactured, or disseminated in any form without express written permission from the publisher. 2009 Sinauer Associates, Inc. UNCORRECTED PAGE PROOFS
CHAPTER 17 Death signal Figure 17.9 Regulation of caspases by IAPs in Drosophila Both initiator and effector caspases are inhibited by IAPs. Many signals that induce apoptosis in Drosophila function by activating members of a family of proteins (Reaper, Hid, and Grim) that inhibit the IAPs, resulting in caspase activation. Reaper, Hid, Grim IAPs Initiator and effector caspases Apoptosis DNA damage ATM Chk2 P p53 P Increased levels of p53 P P P P p53p53 response to growth factor stimulation. These signaling pathways control the fate of a wide variety of cells whose survival is dependent on extracellular growth factors or cell-cell interactions. As already noted, a well-characterized example of programmed cell death in development is provided by the vertebrate nervous system. About 50% of neurons die by apoptosis, with the survivors having received sufficient amounts of survival signals from their target cells. These survival signals are polypeptide growth factors related to nerve growth factor (NGF), which induces bo...
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