celldeath terpse

Tnf and related family members consist of three

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Unformatted text preview: rization. The cytoplasmic This material cannot be copied, reproduced, manufactured, or disseminated in any form without express written permission from the publisher. 2009 Sinauer Associates, Inc. Therapies based on a member of the TNF family are under clinical trial for the treatment of certain cancers. UNCORRECTED PAGE PROOFS 12 CHAPTER 17 FIGURE 17.12 Cell death receptors TNF and other cell death receptor ligands consist of three polypeptide chains, so their binding to cell death receptors induces receptor trimerization. Caspase-8 is recruited to the receptor and activated via interaction with adaptor molecules (the extrinsic pathway of apoptosis). Once activated, caspase-8 can directly cleave and activate effector caspases. In addition, caspase-8 cleaves the BH3-only protein Bid, which activates the intrinsic pathway of apoptosis, leading to caspase-9 activation. TNF TNF receptor Cytosol Adaptor Caspase-8 Bid activation Bid Effector caspase activation Bak/Bax Mitochondrion Caspase-9 activation Effector caspase activation portions of the receptors bind adaptor molecules that in turn bind caspase8. This leads to activation of caspase-8, which can then cleave and activate downstream effector caspases. In some cells, caspase-8 activation and subsequent activation of caspases-3 and -7 is sufficient to induce apoptosis directly. In other cells, however, amplification of the signal is needed. This 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 CELL DEATH AND CELL RENEWAL 13 results from caspase-8 cleavage of the proapoptotic BH3-only protein Bid, leading to Bid activation, permeabilization of mitochondria, and activation of caspase-9, thus amplifying the caspase cascade initiated by direct activation of caspase-8 at cell death receptors. Alternative Pathways of Programmed Cell Death Although apoptosis is the most common form of regulated or programmed cell death, recent research has shown that programmed cell death can also occur by alternative, non-apoptotic mechanisms. One of these alternative pathways of regulated cell death is autophagy. As discussed in Chapter 8, autophagy provides a mechanism for the gradual turnover of the cell's components by the uptake of proteins or organelles into vesicles (autophagosomes) that fuse with lysosomes (see Figure 8.45). In addition, autophagy promotes cell survival under conditions of nutrient deprivation. Under conditions of starvation, activation of autophagy serves to increase the degradation of cellular proteins and organelles, generating energy and allowing their components to be reutilized for essential functions. In other circumstances, however, autophagy provides an alternative to apoptosis as a pathway of cell death. Autophagic cell death does not require caspases and, rather than possessing the distinct morphological features of apoptosis, the dying cells are characterized by an accumulation of lysosomes. Autophagy has been shown to be an important pathway of programmed cell death during salivary gland development in Drosophila and to be induced by infection with some viruses. In addition, autophagy appears to provide an alternative pathway to cell death when apoptosis is blocked. For example, cells of mutant mice lacking Bak and Bax fail to undergo apoptosis in response to stimuli such as DNA damage, as expected since Bak and Bax are required for permeabilization of mitochondria (see Figure 17.8). However, the Bak/Bax-deficient cells die by autophagy instead, suggesting that autophagy may also be activated by cellular stress and provide an alternative to apoptosis under these conditions. It also appears that some forms of necrosis can be a programmed cellular response, rather than simply representing uncontrolled cell lysis as the result of an acute injury. In contrast to unregulated necrosis, these forms of regulated necrotic cell death are induced as a programmed response to stimuli such as infection or DNA damage, which also induce apoptosis. Under these conditions, regulated necrosis may provide an alternative pathway of cell death if apoptosis does not occur. For example, if apoptosis is inhibited, stimulation of the TNF receptor leads to cell death by necrosis. The importance of both autophagy and necrosis as alternatives to apoptosis remains to be fully explored, not only in normal cells but also in diseases such as cancer, heart disease, and neurodegeneration, which involve abnormalities of cell survival. Stem Cells and the Maintenance of Adult Tissues Early development is characterized by the rapid proliferation of embryonic cells, which then differentiate to form the specialized cells of adult tissues and organs. As cells differentiate, their rate of proliferation usually decreases, and most cells in adult animals are arrested in the G0 stage of the cell cycle. However, cells are lost either due to injury or programmed cell death throughout life. In order to maintain a constant number of cells in...
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