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Unformatted text preview: t act to induce caspase activation and promote cell death. There are two groups of these proapoptotic proteins, which differ in function as well as in their extent of homology to Bcl-2. Bcl-2 and the other antiapoptotic family members share four conserved regions called Bcl-2 homology (BH) domains. One group of proapoptotic family members called the "multidomain" proapoptotic proteins have 3 BH domains (BH1, BH2, and BH3), whereas the second group, the "BH3-only" proteins, have only the BH3 domain. The fate of the cell--life or death--is determined by the balance of activity of proapoptotic and antiapoptotic Bcl-2 family members, which act to regulate one another (Figure 17.7). The multidomain proapoptotic family members, such as Bax and Bak, are the downstream effectors that directly induce apoptosis. They are inhibited by interactions with the antiapoptotic family members, such as Bcl-2. The BH3-only family members are upstream members of the cascade, regulated by the signals that induce cell death (e.g., DNA damage) or cell survival (e.g., growth factors). When activated, the BH3-only family members antagonize the antiapoptotic Bcl-2 family members, activating the multidomain proapoptotic proteins and tipping the balance in favor of caspase activation and cell death. Antiapoptotic Proapoptotic multidomain Bcl-2 Bcl-xL Bax Bak Bid Bad Noxa Puma Bim BH4 BH3 BH1 BH2 FIGURE 17.6
BH3 BH1 BH2 Proapoptotic BH3-only BH3 The Bcl-2 family The Bcl-2 family of proteins is divided into three functional groups. Antiapoptotic proteins (e.g., Bcl-2 and Bcl-xL) have four Bcl-2 homology domains (BH1BH4). The multidomain proapoptotic proteins (e.g., Bax and Bak) have three homology domains (BH1BH3), whereas the BH3-only proapoptotic proteins (e.g., Bid, Bad, Noxa, Puma, and Bim) have only one homology domain (BH3). 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 17.7 Regulatory
interactions between Bcl-2 family members In normal cells, the BH3-only proapoptotic proteins are inactive, and the multidomain proapoptotic proteins are inhibited by interaction with antiapoptotic proteins. Cell death signals activate the BH3-only proteins, which then interact with the antiapoptotic proteins, leading to activation of the multidomain proapoptotic proteins and cell death.
Normal cell BH3-only protein (inactive) Apoptotic cell Cell death signal Activation of BH3-only proapoptotic protein BH3-only protein (active) Antiapoptotic protein Multidomain proapoptotic protein Antiapoptotic protein Activation of multidomain proapoptotic protein Apoptosis IAPs were first discovered in virus-infected insect cells as viral proteins that inhibited apoptosis of the host cell. In mammalian cells, members of the Bcl-2 family act at mitochondria, which play a central role in controlling programmed cell death ( Figure 17.8). When activated, Bax and Bak form oligomers in the mitochondrial outer membrane. Formation of these Bax or Bak oligomers leads to the release of cytochrome c from the mitochondrial intermembrane space, either by forming pores or by interacting with other mitochondrial outer membrane proteins. The release of cytochrome c from mitochondria then triggers caspase activation. In particular, the key initiator caspase in mammalian cells (caspase-9) is activated by forming a complex with Apaf-1 in the apoptosome. In mammals, formation of this complex also requires cytochrome c. Under normal conditions of cell survival, cytochrome c is localized to the mitochondrial intermembrane space (see Figure 11.10) while Apaf-1 and caspase-9 are found in the cytosol, so caspase-9 remains inactive. Activation of Bax or Bak results in the release of cytochrome c to the cytosol, where it binds to Apaf-1 and triggers apoptosome formation and caspase-9 activation. Caspases are also regulated by a family of proteins called the IAP, for inhibitor of apoptosis, family. Members of the IAP family directly interact with caspases and suppress apoptosis by either inhibiting caspase activity or by targeting caspases for ubiquitination and degradation in the proteasome. IAPs are present in both Drosophila and mammals (but not C. elegans), and regulation of their activity or expression provides another mechanism for controlling apoptosis. Regulation of IAPs is particularly important in Drosophila, where initiator caspases are chronically activated but held in check by IAPs ( Figure 17.9 ). Many signals that induce apoptosis in Drosophila function by activating proteins that inhibit the IAPs, thus leading to caspase activation. In mammalian cells, the permeabilization of mitoThis 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 9 FIGURE 17.8 The mito...
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