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Life, Death, and the Pursuit of Apoptosis

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Life, Death, and the Pursuit of Apoptosis Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Life, death, and the pursuit of apoptosis Eileen White Center for Advanced Biotechnology and Medicine and Department of Biological Sciences and the Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854 USA Apoptosis or programmed cell death is a genetically con- (Oltvai et al. 1993). Bcl-2 is expressed widely during em- trolled response for cells to commit suicide. The symp- bryogenesis (LeBrun et al. 1993; Novack and Korsmeyer toms of apoptosis are viability loss accompanied by cy- 1994), and its expression becomes more restricted in toplasmic boiling, chromatin condensation, and DNA adult tissues to those requiring long-term survival (stem fragmentation (Wyllie 1980). Pathologists and develop- cells, postmitotic neurons, and proliferating zones; mental biologists have cataloged the occurrences of ap- Hockenbery et al. 1991). optosis for many years based on these defined morpho- Apoptosis plays a major role in normal development, logical features, but what has propelled apoptosis into and it was expected that gain- or loss-of-function of a the forefront of basic research has been the identification death inhibitor such as Bcl-2 would have a phenotype in of genes that control cell death and the appreciation of transgenic mice. Bcl-2 was expected to regulate apopto- the role of apoptosis in development and disease. Regu- sis in lymphoid cells because of the role of Bcl-2 in hu- lation of cell death is essential for normal development man B cell lymphoma. Targeted Bcl-2 overexpression to and is an important defense against viral infection and the lymphoid system extends normal B cell survival the emergence of cancer. Too much cell death can lead to with the persistence of immunoglobulin secreting and impaired development and degenerative diseases, memory cells (Nufiez et al. 1991), partly overcomes the whereas too little cell death car/lead to cancer and per- scid block to B cell development (Strasser et al. 1994), sistent and sustained viral infection. The process of ap- and produces B cell lymphoma (McDonnell et al. 1989; optosis is controlled through the expression of an in- McDonnell and Korsmeyer 1991). Progression to high- creasing number of genes conserved in nematodes grade lymphoma is clonal and frequently coincides with through mammals and viruses. Some gene products are a c-myc translocation. In T cells, ectopic Bcl-2 expres- activators of apoptosis, whereas others are inhibitors and sion produces increased resistance to apoptosis induced the characterization of the function of these gene prod- by glucocoticoids, radiation, anti-CD3, PMA, and iono- ucts will help to define the process of cell death at the mycin and, to a variable degree, affected negative selec- biochemical level. tion (Sentman et al. 1991; Strasser et al. 1991; Siegel et al. 1992). Bcl-2 also has the capacity to promote neuronal The ever-expanding Bcl-2 family of apoptosis regulators survival (Garcia et al. 1992; Allsopp et al. 1993; Farlie et The bcl-2 gene was first identified as part of the most al. 1995). The ability of Bcl-2 to extend cell survival by common translocation in human B cell follicular lym- preventing cell death in vivo in different cell types and in phoma (Bakhshi et al. 1985; Tsujimoto et al. 1985; response to different stimuli suggests that Bcl-2, or Bcl- Cleary et al. 1986) and overexpression of Bcl-2 in trans- 2-like molecules, act at a central, controlling point in the genic animal models mimicked human disease (McDon- pathway to apoptotic cell death. nell et al. 1989; McDonnell and Korsmeyer 1991). Un- Mice with loss-of-function mutations in the bcl-2 gene like other oncogenes characterized at that time, Bcl-2 (knockout mice) have been generated by homologous re- had the unusual property of extending cell survival combination. These mice, which lack Bcl-2 protein, are rather than stimulating cell proliferation (Vaux et al. surprisingly normal at birth, but possess impaired kid- 1988; Hockenbery et al. 1990). Bcl-2 has since been ney development, and later progress to polycystic kidney shown to enhance cell survival by inhibiting apoptosis disease. The absence of Bcl-2 also produces catastrophic induced under a wide variety of circumstances, suggest- postnatal immune function failure attributable to dra- ing that it is a ubiquitous inhibitor of cell death triggered matic loss of mature B and T cells through apoptosis by multiple routes. (Nakayama et al. 1993, 1994; Veis et al. 1993; Kamada et Bcl-2 possesses a putative transmembrane domain at al. 1995). Hair hypopigmentation arises at the second its carboxyl terminus and is found associated with mi- hair follicle cycle, apparently because of death of mela- tochondrial, endoplasmic reticulum, and nuclear mem- nocytes (Kamada et al. 1995). Distortion of the small branes. Removal of the transmembrane region of Bcl-2 intestines, probably because of impaired survival of the prevents membrane targeting, whereas the mutant pro- progenitor cells at the base of the crypts, has also been tein retains partial activity, suggesting that membrane reported (Kamada et al. 1995). The unexpected ability of targeting of Bcl-2 is not absolutely critical for function the bcl-2 knockout mice to progress through develop- GENES & DEVELOPMENT 10:1-15 © 1996 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/96 $5.00 1 Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press White ment without severe difficulty suggests possible func- White et al. 1992; Boyd et al. 1994; Chiou et al. 1994b). tional redundancy or that other Bcl-2 family members Multiple sequence alignment of the Bcl-2 family mem- may have a more critical role. Thus, inappropriate gain bers and mutagenesis have identified three conserved re- of Bcl-2 function is associated with cancer, whereas loss gions, Bcl-2 homology region 1, 2, and 3 IBH1, BH2, and of Bcl-2 function has dire but restricted consequences to BH3), that are required for regulation of apoptosis and normal development. protein-protein interactions (see below). There has been much speculation regarding the bio- The bcl-x gene is highly related to bcI-2 and also func- chemical mode of action of Bcl-2. Initial suggestions tions to regulate cell death (Boise et al. 1993). bcl-x tran- were that Bcl-2 may work through scavenging reactive scripts are alternatively spliced into long {L) and short {S1 oxygen radicals to prevent apoptosis (Hockenbery et al. forms. The protein product of the long form derived from 1993; Kane et al. 1993). This proposal was based largely the bcl-XL splice variant functionally resembles bcl-2 as on the ability of Bcl-2 to mitigate cell death induced by a potent inhibitor of cell death. The product derived from oxidative damage, although it remained possible that the the alternatively spliced short form, the bcl-x s splice oxidative damage was a downstream consequence of cell variant, antagonizes cell death inhibition by the bcl-xL death, minimized by Bcl-2 through blockade of the death and bcl-2 products (Boise et al. 1993). The BH1 and BH2 process. Further evidence suggests that Bcl-2 can inhibit conserved regions in the Bcl-2 family are spliced out of cell death in cells that lack mitochondrial DNA and Bcl-x s suggesting that it may act directly or indirectly as thereby respiration (Jacobson et al. 1993), and in the pres- a dominant-interfering Bcl-2 or Bcl-xL antagonist. Bcl-x ence of nearly anaerobic conditions (Jacobson and Raft is expressed widely in development, particularly in brain 1995; Shimizu et al. 1995). Thus, the mechanism by and kidney, with the highest levels expressed in the thy- which Bcl-2 works does not involve direct inhibition of mus in adult tissue (Boise et al. 1993; Krajewski et al. reactive oxygen radical accumulation. Instead, oxidative 1994; Motoyama et al. 1995). In contrast to the bcl-2 damage may be a downstream event in the cell death knockout mice, the bcl-x knockout mice have an em- process. Although a means to induce apoptosis through bryonic lethal phenotype around embryonic day 13 (El3) the generation of reactive oxygen species may exist, it with massive apoptosis in the brain and spinal cord, par- may feed into a common pathway to control apoptosis ticularly among differentiating neurons and in the he- that can be inhibited by Bcl-2. matopoietic system (Motoyama et al. 1995). Chimeric bcl-2 is no longer a single entity but one member of a mice nullizygous for bcl-x in the lymphoid system dem- growing multigene family (Table 1 }, with multiple rep- onstrated the requirement for bcl-x expression for main- resentatives in mammals: bcl-x (Boise et al. 1993), mcl-1 taining the life span of immature but not mature lym- (Kozopas et al. 1993), bax (Oltvai et al~ 1993), A1 (Lin et phocytes (Motoyama et al. 1995). Thus, bcl-x and bcl-2 al. 1993), bak (Chittenden et al. 1995a; Farrow et al. are complementary in function as apoptosis inhibitors in 1995; Kiefer et al. 1995), bad (E. Yang et al. 1995); bcl-w mouse development. (S. Gory, pets. comm.), and the nematode Caenorhabdi- Mcl-1 was cloned in a screen for genes with increased tis elegans: ced-9 (Hengartner et al. 1992; Hengartner expression when a human myeloblastic leukemia cell and Horvitz 1994a). Viral homologs of Bcl-2 have been line was induced to differentiate by phorbol ester (Kozo- found in Epstein-Barr virus IEBV) (BHRF1; Cleary et al. pas et al. 1993). Mcl-1 is considerably larger than Bcl-2. 1986), African swine fever virus (AFSV)(LMWS-HL; Nei- The carboxy-terminal half of Mcl-1 displays homology lan et al.
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