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Unformatted text preview: f a DNase, which when activated is responsible for fragmentation of nuclear DNA. In addition, caspases cleave nuclear lamins, leading to fragmentation of the nucleus; cytoskeletal proteins, leading to disruption of the cytoskeleton, membrane blebbing, and cell fragmentation; and Golgi matrix proteins, leading to fragmentation of the Golgi apparatus. The translocation of phosphatidylserine to the cell surface is also dependent on caspases, although the caspase target(s) responsible for this plasma membrane alteration have not yet been identified. Apoptosis Ced-9 Ced-4 Ced-3 FIGURE 17.3 Programmed cell death in C. elegans Genetic analysis identified three genes that play key roles in programmed cell death during development of C. elegans. Two genes, ced-3 and ced-4, are required for cell death, whereas ced-9 inhibits cell death. The Ced-9 protein acts upstream of Ced-4, which activates Ced-3. 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 FIGURE 17.4 Caspase targets Caspases cleave over 100 cellular proteins to induce the morphological alterations characteristic of apoptosis. Caspase targets include an inhibitor of DNase (ICAD), nuclear lamins, cytoskeletal proteins, and Golgi matrix proteins.
ICAD Inhibitor of DNase DNA fragmentation Nuclear lamins Fragmentation of nucleus Caspases Cytoskeletal proteins Actin, myosin, a-actinin, tubulin, vimentin Cell fragmentation, membrane blebbing Golgi matrix proteins Fragmentation of Golgi Ced-3 is the only caspase in C. elegans. However, Drosophila and mammals contain families of at least seven caspases, classified as either initiator or effector caspases, that function in a cascade to bring about the events of apoptosis. All caspases are synthesized as inactive precursors that can be converted to the active form by proteolytic cleavage, catalyzed by other caspases. Initiator caspases are activated directly in response to the various signals that induce apoptosis, as discussed later in this chapter. The initiator caspases then cleave and activate the effector caspases, which are responsible for digesting the cellular target proteins that mediate the events of apoptosis (see Figure 17.4). The activation of an initiator caspase therefore starts off a chain reaction of caspase activation leading to death of the cell. Genetic analysis in C. elegans initially suggested that Ced-4 functioned as an activator of the caspase Ced-3. Subsequent studies have shown that Ced4 and its mammalian homolog (Apaf-1) bind to caspases and promote their activation. In mammalian cells, the key initiator caspase (caspase-9) is activated by binding to Apaf-1 in a multisubunit complex called the apoptosome (Figure 17.5). Formation of this complex in mammals also requires Cytochrome c Caspase-9 (initiator caspase) Apaf-1 Pro-caspase-3 Active caspase-3 Effector caspase Apoptosis FIGURE 17.5 Caspase activation The mammalian initiator caspase-9 is activated as a complex with Apaf-1 and cytochrome c in the apoptosome. Caspase-9 then cleaves and activates effector caspases, such as caspase-3. 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 7 cytochrome c, which is released from mitochondria by stimuli that trigger apoptosis (discussed in the following section). Once activated in the apoptosome, caspase-9 cleaves and activates downstream effector caspases, such as caspase-3 and caspase-7, eventually resulting in cell death. Central Regulators of Apoptosis: The Bcl-2 Family
The third gene identified as a key regulator of programmed cell death in C. elegans, ced-9, was found to be closely related to a mammalian gene called bcl-2, which was first identified in 1985 as an oncogene that contributed to the development of human B cell lymphomas (cancers of B lymphocytes). In contrast to other oncogene proteins, such as Ras, that stimulate cell proliferation (see Molecular Medicine, Chapter 15), Bcl-2 was found to inhibit apoptosis. Ced-9 and Bcl-2 were thus similar in function, and the role of Bcl2 as a regulator of apoptosis first focused attention on the importance of cell survival in cancer development. As discussed further in the next chapter, we now recognize that cancer cells are generally defective in the normal process of programmed cell death and that their inability to undergo apoptosis is as important as their uncontrolled proliferation in the development of malignant tumors. Mammals encode a family of approximately 20 proteins related to Bcl-2, which are divided into three functional groups (Figure 17.6). Some members of the Bcl-2 family (antiapoptotic family members)--like Bcl-2 itself-- function as inhibitors of apoptosis and programmed cell death. Other members of the Bcl-2 family, however, are proapoptotic proteins tha...
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