Further Reading

CHAPTER 1

Cell Death Nomenclature

Andre N. 2003. Hippocrates of Cos and apoptosis. Lancet 361: 1306.
A note on an early use of “apoptosis” in medicine.

Degli-Esposti M. 1998. Apoptosis: Who was first? Cell Death Differ 5: 719.
A hunt for the origins of the word “apoptosis.”

Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, et al. 2009. Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16: 3–11.
More than simply nomenclature, this review outlines the different types of cell death and problems with their classification.

Lockshin RA, Zakeri Z. 2004. Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36: 2405–2419.
A useful review of the types of cell death.

History of Apoptosis

Diamantis A, Magiorkinis E, Sakorafas GH, Androutsos G. 2008. A brief history of apoptosis: From ancient to modern times. Onkologie 31: 702–706.
Not essential reading, but an interesting overview of the study of apoptosis.

Horvitz HR. 2003. Nobel lecture. Worms, life and death. Biosci Rep 23: 239–303.
The modern study of apoptosis was ignited by the identification of genes that control cell death during development in the nematode C. elegans. This is the Nobel lecture that describes those studies.

Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239–257.
This is the original paper formally describing apoptosis.

Saunders JW Jr. 1966. Death in embryonic systems. Science 154: 604–612.
A classic early overview of the role of cell death in development.

CHAPTER 2

Caspases

Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P. 2007. Caspases in cell survival, proliferation and differentiation. Cell Death Differ 14: 44–55.
A review of the caspases and their functions in life and death.

Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. 1993. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 β-converting enzyme. Cell 75: 641–652.
The original landmark paper that identified caspases as being important in apoptosis.

Fernandes-Alnemri T, Litwack G, Alnemri ES. 1994. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 β-converting enzyme. J Biol Chem 269: 30761–30764.
The first description of mammalian caspase-3, originally called CPP32.

Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J. 1996. Human ICE/CED-3 protease nomenclature. Cell 87: 171.

Eckhart L, Ballaun C, Hermann M, VandeBerg JL, Sipos W, Uthman A, Fischer H. Tschachler E. 2008. Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire. Mol Biol Evol 25: 831–841.
An overview of the evolutionary relationships among mammalian caspases, including caspase-15, -16, -17, and -18.

Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA. 1996. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384: 368–372.
The first knockout of caspase-3 (called CPP32) and effects on development.

Caspase Specificities

Timmer JC, Salvesen GS. 2007. Caspase substrates. Cell Death Differ 14: 66–72.
Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T, Garcia-Calvo M, Houtzager VM, Nordstrom PA, Roy S, Vaillancourt JP, et al. 1997. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 272: 17907–17911.
The identification of caspase preferences through the use of a combinatorial peptide library.

Mahrus S, Trinidad JC, Barkan DT, Sali A, Burlingame AL, Wells JA. 2008. Global sequencing of proteolytic cleavage sites in apoptosis by specific labeling of protein N termini. Cell 134: 866–876.
Another approach to characterization of caspase substrates.

Functional Caspase Substrates

Luthi AU, Martin SJ. 2007. The CASBAH: A searchable database of caspase substrates. Cell Death Differ 14: 641–650.
An introduction to a searchable database of all known caspase substrates.

Sakahira H, Enari M, Nagata S. 1998. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391: 96–99.
One of the original descriptions of the iCAD–CAD system and its role in DNA fragmentation during apoptosis.

Zhang J, Liu X, Scherer DC, van Kaer L, Wang X, Xu M. 1998. Resistance to DNA fragmentation and chromatin condensation in mice lacking the DNA fragmentation factor 45. Proc Natl Acad Sci 95: 12480–12485.
A clear demonstration of the role of iCAD/DFF45 in DNA fragmentation versus cell death.

Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J. 2001. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 3: 346–352.
One of the original descriptions of ROCK as a caspase substrate and its role in blebbing during apoptosis.

Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF. 2001. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3: 339–345.
See above.

Kothakota S, Azuma T, Reinhard C, Klippel A, Tang A, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, et al. 1997. Caspase-3-generated fragment of gelsolin: Effector of morphological change in apoptosis. Science 278: 294–298.
The role of gelsolin in blebbing during apoptosis.

Ricci JE, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Scheffler IE, Ellisman MH, Green DR. 2004. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117: 773–786.
The original description of NDUFS1 as a mitochondrial caspase substrate.

CHAPTER 3

Mechanisms of Caspase Activation

Fuentes-Prior P, Salvesen GS. 2004. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 384: 201–232.

Pop C, Salvesen GS. 2009. Human caspases: Activation, specificity, and regulation. J Biol Chem 284: 21777–21781.

Salvesen GS, Riedl SJ. 2008. Caspase mechanisms. Adv Exp Med Biol 615: 13–23.
Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H. 2007. The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu Rev Immunol 25: 561–586.
An extensive overview of the structures involved in caspase activation. Several of the mechanisms discussed are covered in later chapters.

Induced Proximity

Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. 1998. An induced proximity model for caspase-8 activation. J Biol Chem 273: 2926–2930.
The original description of induced proximity, applied to caspase-8.

Stennicke HR, Deveraux QL, Humke EW, Reed JC, Dixit VM, Salvesen GS. 1999. Caspase-9 can be activated without proteolytic processing. J Biol Chem 274: 8359–8362.

Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM, Ricci JE, Edris WA, Sutherlin DP, Green DR, et al. 2003. A unified model for apical caspase activation. Mol Cell 11: 529–541.

Caspase Activation Cascades

Fernandes-Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, et al. 1996. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci 93: 7464–7469.
One of the first papers to show a caspase activation cascade, with caspase-8 (called Mch4) cleaving and activating caspase-3 (called CPP32) and caspase-7 (called Mch3).

Slee EA, Adrain C, Martin SJ. 1999. Serial killers: Ordering caspase activation events in apoptosis. Cell Death Differ 6: 1067–1074.

Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, et al. 1999. Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144: 281–292.
The order of caspase cleavage following activation of caspase-9 in a cell extract (see Chapter 4 for the initial activation mechanism).

IAPs

Salvesen GS, Riedl SJ. 2007. Caspase inhibition, specifically. Structure 15: 513–514.
An overview of IAPs and other intracellular caspase inhibitors.

Silke J, Vaux DL. 2001. Two kinds of BIR-containing protein: Inhibitors of apoptosis, or required for mitosis. J Cell Sci 114: 1821–1827.
An important distinction between different IAPs and their functions.

Vaux DL, Silke J. 2005. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6: 287–297.
Orme M, Meier P. 2009. Inhibitor of apoptosis proteins in Drosophila: Gatekeepers of death. Apoptosis 14: 950–960.

Hay BA, Wassarman DA, Rubin GM. 1995. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell 83: 1253–1262.
The discovery of IAPs.

Deveraux QL, Takahashi R, Salvesen GS, Reed JC. 1997. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304.
The first paper to show that XIAP is a caspase inhibitor.

Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS. 2001. Structural basis for the inhibition of caspase-3 by XIAP. Cell 104: 791–800.

CHAPTER 4

Mitochondria and Cell Death

Tait SWG, Green DR. 2010. Mitochondria and cell death: Outer membrane permeabilization and beyond. Nat Rev Cell Mol Biol 11: 621–632.
A detailed review of MOMP and its consequences.

Green DR, Kroemer G. 2004. The pathophysiology of mitochondrial cell death. Science 305: 626–629.
Wallace DC, Fan W. 2009. The pathophysiology of mitochondrial disease as modeled in the mouse. Genes Dev 23: 1714–1736.
This review discusses how defects in mitochondrial function affect cell survival and death.

Cytochrome c and the Apoptosome

Green DR. 1998. Apoptotic pathways: The roads to ruin. Cell 94: 695–698.
An early review describing the mitochondrial pathway of apoptosis.

Green DR. 2005. Apoptotic pathways: Ten minutes to dead. Cell 121: 671–674.
A later review that incorporates MOMP and additional players into the mitochondrial pathway of apoptosis.

Liu X, Kim CN, Yang J, Jemmerson R, Wang X. 1996. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 86: 147–157.
The original paper showing that cytochrome c induces caspase activation.

Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. 1997. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90: 405–413.
The identification and characterization of APAF1.

Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. 1997. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479–489.
The interaction between APAF1 and caspase-9 leading to caspase activation was first described in this paper.

Yuan S, Yu X, Topf M, Ludtke SJ, Wang X, Akey CW. 2010. Structure of an apoptosome-procaspase-9 CARD complex. Structure 18: 571–583.

MOMP

Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR. 2000. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2: 156–162.
The original paper demonstrating MOMP in cells using fluorescent cytochrome c.

Waterhouse NJ, Goldstein JC, von Ahsen O, Schuler M, Newmeyer DD, Green DR. 2001. Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol 153: 319–328.
The immediate consequences of MOMP for mitochondria are explored.

Smac/DIABLO and Omi

Verhagen AM, Kratina TK, Hawkins CJ, Silke J, Ekert PG, Vaux DL. 2007. Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ 14: 348–357.

Green DR. 2000. Apoptotic pathways: Paper wraps stone blunts scissors. Cell 102: 1–4.
Du C, Fang M, Li Y, Li L, Wang X. 2000. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102: 33–42.
The original description of Smac, published with the original description of the mouse homolog DIABLO.

Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL. 2000. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43–53.
See above.

Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, et al. 2002. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein–caspase interaction. J Biol Chem 277: 432–438.
One of several papers initially describing Omi and its role in apoptosis.

Caspase-independent Cell Death

Chipuk JE, Green DR. 2005. Do inducers of apoptosis trigger caspase-independent cell death? Nat Rev Mol Cell Biol 6: 268–275.

Lartigue L, Kushnareva Y, Seong Y, Lin H, Faustin B, Newmeyer DD. 2009. Caspase-independent mitochondrial cell death results from loss of respiration, not cytotoxic protein release. Mol Biol Cell 20: 4871–4884.
A study showing that MOMP-induced, caspase-independent cell death is a consquence of loss of mitochonrial function.

Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, et al. 1999. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397: 441–446.
The initial characterization of AIF.

Li LY, Luo X, Wang X. 2001. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412: 95–99.
Initial description of endonuclease G and its proposed role in caspase-independent cell death.

Mitochondrial Permeability Transition
Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL. 2009. Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787: 1395–1401.
An overview of the permeability transition in cell death, but one that suggests roles in apoptosis.

Kroemer G, Galluzzi L, Brenner C. 2007. Mitochondrial membrane permeabilization in cell death. Physiol Rev 87: 99–163.
An attempt to unify concepts of MOMP and MPT in cell death.

Tsujimoto Y, Nakagawa T, Shimizu S. 2006. Mitochondrial membrane permeability transition and cell death. Biochim Biophys Acta 1757: 1297–1300.

Leung AW, Halestrap AP. 2008. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777: 946–952.

Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y. 2005. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658.
One of several papers showing that MPT has roles in necrosis but not apoptosis.

Apoptosomes in Worms and Flies

Bao Q, Shi Y. 2007. Apoptosome: A platform for the activation of initiator caspases. Cell Death Differ 14: 56–65.

Qi S, Pang Y, Hu Q, Liu Q, Li H, Zhou Y, He T, Liang Q, Liu Y, Yuan X, et al. 2010. Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4. Cell 141: 446–457.

Yu X, Wang L, Acehan D, Wang X, Akey CW. 2006. Three-dimensional structure of a double apoptosome formed by the Drosophila Apaf-1 related killer. J Mol Biol 355: 577–589.

Rodriguez A, Chen P, Oliver H, Abrams JM. 2002. Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf-1 homolog, Dark. EMBO J 21: 2189–2197.
The role of DIAP1 in restraining ARK (called “Dark”)-induced caspase activity in flies.

Rodriguez A, Oliver H, Zou H, Chen P, Wang X, Abrams JM. 1999. Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway. Nat Cell Biol 1: 272–279.
The identification of ARK (called “Dark”).

Yuan J, Horvitz HR. 1992. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116: 309–320.
The original characterization of CED4.

Chinnaiyan AM, Chaudhary D, O’Rourke K, Koonin EV, Dixit VM. 1997. Role of CED-4 in the activation of CED-3. Nature 388: 728–729.
One of the original papers showing that CED4 biochemically activates CED3.

CHAPTER 5

BCL-2 Proteins

Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. 2010. The BCL-2 family reunion. Mol Cell 37: 299–310.

Youle RJ, Strasser A. 2008. The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47–59.

Anti-apoptotic BCL-2 Proteins

Vaux DL, Cory S, Adams JM. 1988. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335: 440–442.
The first paper to show that BCL-2 preserves cell survival in primary and transformed cells.

Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. 1990. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336.
The first paper to show that BCL-2 is associated with mitochondria (the original assertion that it is on the inner membrane was due to an artifact) and that BCL-2 inhibits apoptosis.

Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. 1997. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275: 1132–1136.
One of two papers (see below) identifying the role of BCL-2 in blocking the release of cytochrome c from mitochondria.

Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. 1997. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 275: 1129–1132.
See above.

Vaux DL, Weissman IL, Kim SK. 1992. Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science 258: 1955–1957.
One of two papers that showed that CED9 and BCL-2 are functionally equivalent in nematodes. Although BCL-2 does not bind to CED4, it can sequester EGL1, which was not shown until later.

Hengartner MO, Horvitz HR. 1994. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76: 665–676.
See above.

Jabbour AM, Puryer MA, Yu JY, Lithgow T, Riffkin CD, Ashley DM, Vaux DL, Ekert PG, Hawkins CJ. 2006. Human Bcl-2 cannot directly inhibit the Caenorhabditis elegans Apaf-1 homologue CED-4, but can interact with EGL-1. J Cell Sci 119: 2572–2582.
See above.

Pro-apoptotic BCL-2 Effectors
Oltvai ZN, Milliman CL, Korsmeyer SJ. 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609–619.
The discovery of BAX.

Chittenden T, Harrington EA, O’Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC. 1995. Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374: 733–736.
The discovery of BAK.

Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. 2001. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292: 727–730.
This paper showed that BAX and BAK are necessary for MOMP and apoptosis via the mitochondrial pathway.

BH3-only Proteins

Giam M, Huang DC, Bouillet P. 2008. BH3-only proteins and their roles in programmed cell death. Oncogene (suppl 1) 27: S128–S136.

Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ, Ellerby LM, Bredesen D, Freeze H, Abrahamson M, et al. 2001. Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J Biol Chem 276: 3149–3157.
BID as a protease sensor for engaging the mitochondrial pathway of apoptosis.

Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW, Dikkes P, Korsmeyer SJ, Greenberg ME. 2002. Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3: 631–643.
The regulation of BAD by survival factor signaling.

Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A. 1999. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735–1738.
The BIM knockout mouse illustrates roles for this protein in apoptosis.

Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A. 1999. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3: 287–296.
The association of BIM with the cytoskeleton.

Conradt B, Horvitz HR. 1998. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93: 519–529.
EGL1 is a BH3-only protein in nematodes.

BCL-2 Protein Interactions

Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. 2002. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183–192.
The proposal of the “direct activator/derepressor” (called “sensitizer”) model of BH3-only protein function.

Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. 2005. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17: 393–403.
The “neutralization” model of BH3-only protein function and specificities of BH3-only proteins for different anti-apoptotic proteins.

Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. 2005. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19: 1294–1305.
The “neutralization” model of BH3-only protein function.

Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD. 2002. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111: 331–342.
Biochemical characterization of BAX activation and membrane permeabilization.

Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. 2009. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36: 487–499.
Further analysis of the “direct activator/derepressor” model of BH3-only protein function.

Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B, Andrews DW. 2008. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135: 1074–1084.
Use of FRET technology to characterize derepression and direct activation of BAX.

Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, et al. 2008. BAX activation is initiated at a novel interaction site. Nature 455: 1076–1081.
Structural analysis of the binding of the BIM BH3 region to BAX and early steps in BAX activation.

Other Functions of the BCL-2 Family
Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, Youle RJ. 2002. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159: 931–938.
Characterization of interactions between BAX and proteins involved in mitochondrial fission and fusion.

Sheridan C, Delivani P, Cullen SP, Martin SJ. 2008. Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome c release. Mol Cell 31: 570–585.
Evidence that mitochondrial fission occurs at the time of MOMP, but is not required for permeabilization.

Rong Y, Distelhorst CW. 2008. Bcl-2 protein family members: Versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol 70: 73–91.

Chen R, Valencia I, Zhong F, McColl KS, Roderick HL, Bootman MD, Berridge MJ, Conway SJ, Holmes AB, Mignery GA, et al. 2004. Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J Cell Biol 166: 193–203.
Characterization of the regulation of calcium homeostasis by BCL-2.

Levine B, Sinha S, Kroemer G. 2008. Bcl-2 family members: Dual regulators of apoptosis and autophagy. Autophagy 4: 600–606.

Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B. 2005. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.
A mechanism for the regulation of autophagy by BCL-2. Autophagy is covered in more detail in Chapter 8.

Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL. 2008. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283: 10892–10903.
How BCL-2 interactions can cause autophagic removal of mitochondria.

Cuconati A, White E. 2002. Viral homologs of BCL-2: Role of apoptosis in the regulation of virus infection. Genes Dev 16: 2465–2478.

CHAPTER 6

Death Receptors

Wilson NS, Dixit V, Ashkenazi A. 2009. Death receptor signal transducers: Nodes of coordination in immune signaling networks. Nat Immunol 10: 348–355.

Guicciardi ME, Gores GJ. 2009. Life and death by death receptors. FASEB J 23: 1625–1637.

Falschlehner C, Ganten TM, Koschny R, Schaefer U, Walczak H. 2009. TRAIL and other TRAIL receptor agonists as novel cancer therapeutics. Adv Exp Med Biol 647: 195–206.

Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP. 1999. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17: 331–367.

Banner DW, D’Arcy A, Janes W, Gentz R, Schoenfeld HJ, Broger C, Loetscher H, Lesslauer W. 1993. Crystal structure of the soluble human 55 kd TNF receptor-human TNF β complex: Implications for TNF receptor activation. Cell 73: 431–445.

Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O’Connell M, Kelley RF, Ashkenazi A, de Vos AM. 1999. Triggering cell death: The crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 4: 563–571.
The structure of TRAIL shows a role for zinc that is not seen in other TNF-family ligands.

Death Receptor Signaling

Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. 1998. An induced proximity model for caspase-8 activation. J Biol Chem 273: 2926–2930.
The activation of caspase-8 by FADD-mediated induced proximity.

Micheau O, Tschopp J. 2003. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114: 181–190.
The identification of two complexes involved in TNFR signaling.

Karin M, Gallagher E. 2009. TNFR signaling: Ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes. Immunol Rev 228: 225–240.
An in-depth overview of TNFR signaling to NF-κB and other pathways.

Defects in the CD95 Pathway Cause Disease

Bidere N, Su HC, Lenardo MJ. 2006. Genetic disorders of programmed cell death in the immune system. Annu Rev Immunol 24: 321–352.
An overview of diseases in mice and humans caused by defects in CD95, CD95L, and associated caspases.

Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314–317.
Defects in CD95 (called “Fas antigen”) are responsible for a lymphoaccumulative disease in mice (originally thought to be a lymphoproliferation defect).

Lynch DH, Watson ML, Alderson MR, Baum PR, Miller RE, Tough T, Gibson M, Davis-Smith T, Smith CA, Hunter K, et al. 1994. The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity 1: 131–136.
Defects in CD95L (called “Fas ligand”) are responsible for a lymphoaccumulative disease in mice.

Death Receptors and the Mitochondrial Pathway

Li H, Zhu H, Xu CJ, Yuan J. 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.
Two papers identified BID as a target for caspase-8, linking the death receptor and mitochondrial pathways of apoptosis.

Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. 1998. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490.
See above.

Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME. 1998. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17: 1675–1687.
The description of two cell types (“type I and type II”) in which the mitochondrial pathway is dispensable (type I) or required (type II) for death receptor–induced apoptosis.

Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, et al. 2009. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460: 1035–1039.
Inhibition of XIAP is required for apoptosis induced by CD95 (called “Fas”) in type II cells in mice.

CHAPTER 7

The Inflammatory Caspases

Kersse K, Vanden Berghe T, Lamkanfi M, Vandenabeele P. 2007. A phylogenetic and functional overview of inflammatory caspases and caspase-1-related CARD-only proteins. Biochem Soc Trans 35: 1508–1511.
An overview of the inflammatory caspases and the molecules that interact with them.

Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA, et al. 1992. Molecular cloning of the interleukin-1 β converting enzyme. Science 256: 97–100.
Two papers describing the identification of caspase-1, the first caspase discovered.

Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J, et al. 1992. A novel heterodimeric cysteine protease is required for interleukin-1 β processing in monocytes. Nature 356: 768–774.
See above.

Dinarello CA. 2009. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27: 519–550.
Interleukin-1 is a major target of caspase-1, and an understanding of its biological roles provides a context for appreciating the significance of caspase-1 function.

Keller M, Ruegg A, Werner S, Beer HD. 2008. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132: 818–831.
The role of caspase-1 in secretion of proteins that lack conventional secretory signal sequences.

TLRs and NLRs
Fukata M, Vamadevan AS, Abreu MT. 2009. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol 21: 242–253.

O’Neill LA. 2008. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 226: 10–18.

Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394–397.
The original paper describing mammalian Toll-like receptors and their importance in the immune response.

Inflammasomes
Schroder K, Tschopp J. 2010. The inflammasomes. Cell 140: 821–832.

Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G. 2009. The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10: 241–247.

Martinon F, Burns K, Tschopp J. 2002. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL- β. Mol Cell 10: 417–426.
The first paper describing an inflammasome, which in this case involved NLRP1 (called “Nalp1”). Although this inflammasome includes caspase-5, all others described do not.

Jin C, Flavell RA. 2010. Molecular mechanism of NLRP3 inflammasome activation. J Clin Immunol (in press).
Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. 2004. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20: 319–325.
A description of the NLRP3 (called “NALP3”) inflammasome.

Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430: 213–218.
A description of the IPAF inflammasome.

Apoptosis via Caspase-1 Activation
Kepp O, Galluzzi L, Zitvogel L, Kroemer G. 2010. Pyroptosis—A cell death modality of its kind? Eur J Immunol 40: 627–630.

Bergsbaken T, Fink SL, Cookson BT. 2009. Pyroptosis: Host cell death and inflammation. Nat Rev Microbiol 7: 99–109.

Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES. 2007. The pyroptosome: A supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ 14: 1590–1604.
This paper proposes that caspase-1–mediated cell death is favored by oligomers of ASC, forming independently of other adapter proteins.

Caspase-2

Kumar S. 2009. Caspase 2 in apoptosis, the DNA damage response and tumour suppression: Enigma no more? Nat Rev Cancer 9: 897–903.
Possible roles for caspase-2 in apoptosis and other phenomena.

Krumschnabel G, Manzl C, Villunger A. 2009. Caspase-2: Killer, savior and safeguard—Emerging versatile roles for an ill-defined caspase. Oncogene 28: 3093–3096.
Additional views of roles for caspase-2.

Tinel A, Tschopp J. 2004. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304: 843–846.
The first characterization of a complex responsible for activating caspase-2.

Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, Wu H. 2007. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128: 533–546.
Bouchier-Hayes L, Oberst A, McStay GP, Connell S, Tait SW, Dillon CP, Flanagan JM, Beere HM, Green DR. 2009. Characterization of cytoplasmic caspase-2 activation by induced proximity. Mol Cell 35: 830–840.
The activation of caspase-2 by several stressors, analyzed using a live cell–imaging technique.

CHAPTER 8

Nonapoptotic Cell Death

Degterev A, Yuan J. 2008. Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 9: 378–390.
See also the reviews listed under Additional Reading for Chapter 1.

Necrosis

Silva MT, do Vale A, dos Santos NM. 2008. Secondary necrosis in multicellular animals: An outcome of apoptosis with pathogenic implications. Apoptosis 13: 463–482.

Bouchard VJ, Rouleau M, Poirier GG. 2003. PARP-1, a determinant of cell survival in response to DNA damage. Exp Hematol 31: 446–454.

Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: Mechanisms and significance. Annu Rev Physiol 72: 19–44.
Overview of ischemia/reperfusion injury in the heart and other roles for cell death in heart disease.

Szydlowska K, Tymianski M. 2010. Calcium, ischemia and excitotoxicity. Cell Calcium 47: 122–129.
Kim YS, Morgan MJ, Choksi S, Liu ZG. 2007. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell 26: 675–687.

Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, et al. 1997. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3: 1089–1095.
A connection between ischemia/reperfusion injury and PARP.

Programmed Necrosis (Necroptosis)
Christofferson DE, Yuan J. 2009. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22: 263–268.

Declercq W, Vanden Berghe T, Vandenabeele P. 2009. RIP kinases at the crossroads of cell death and survival. Cell 138: 229–232.

Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. 2000. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1: 489–495.
The first description of RIPK-dependent cell death, in this case induced by CD95 (called “Fas”).

Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J. 2008. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135: 1311–1323.
An approach to characterization of the mechanism of RIPK-dependent necrosis.

Autophagy

He C, Klionsky DJ. 2009. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43: 67–93.

Eskelinen EL. 2008. New insights into the mechanisms of macroautophagy in mammalian cells. Int Rev Cell Mol Biol 266: 207–247.

Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. 2009. Dynamics and diversity in autophagy mechanisms: Lessons from yeast. Nat Rev Mol Cell Biol 10: 458–467.

Suzuki K, Ohsumi Y. 2010. Current knowledge of the pre-autophagosomal structure (PAS). FEBS Lett 584: 1280–1286.

Autophagic Cell Death

Levine B, Yuan J. 2005. Autophagy in cell death: An innocent convict? J Clin Invest 115: 2679–2688.

Baehrecke EH. 2005. Autophagy: Dual roles in life and death? Nat Rev Mol Cell Biol 6: 505–510.

Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ. 2004. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304: 1500–1502.
The first paper suggesting that caspase-8 inhibits autophagy-dependent cell death, which ultimately turned out to be RIPK-dependent cell death. The relationships between these modes of cell death remain unresolved.

Mitotic Catastrophe

Vakifahmetoglu H, Olsson M, Zhivotovsky B. 2008. Death through a tragedy: Mitotic catastrophe. Cell Death Differ 15: 1153–1162.

Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. 2004. Cell death by mitotic catastrophe: A molecular definition. Oncogene 23: 2825–2837.

Kirsch DG, Santiago PM, di Tomaso E, Sullivan JM, Hou WS, Dayton T, Jeffords LB, Sodha P, Mercer KL, Cohen R, et al. p53 controls radiation-induced gastrointestinal syndrome in mice independent of apoptosis. Science 327: 593–596.
Cell death in the intestines of BAX–BAK double-deficient mice may be a form of mitotic catastrophe. p53 is discussed in Chapter 11.

CHAPTER 9

Engulfment of Dying Cells

Elliott MR, Ravichandran KS. 2010. Clearance of apoptotic cells: Implications in health and disease. J Cell Biol 189: 1059–1070.

Erwig LP, Henson PM. 2008. Clearance of apoptotic cells by phagocytes. Cell Death Differ 15: 243–250.
Ravichandran KS, Lorenz U. 2007. Engulfment of apoptotic cells: Signals for a good meal. Nat Rev Immunol 7: 964–974.
A particularly thorough overview of the mechanisms of engulfment.

Lauber K, Blumenthal SG, Waibe Ml, Wesselborg S. 2004. Clearance of apoptotic cells: Getting rid of the corpses. Mol Cell 14: 277–287.

Find-me Signals

Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK, Marini P, Wiedig C, Zobywalski A, Baksh S, et al. 2003. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113: 717–730.
Identification of lysophosphocholine as a “find-me” signal and one way in which it is produced following caspase activation.

Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, et al. 2009. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461: 282–286.
Identification of ATP as a “find-me” signal.

Bind-me Signals

Bevers EM, Williamson PL. 2010. Phospholipid scramblase: An update. FEBS Lett 584: 2724–2730.
The mechanism of caspase-dependent phosphatidylserine externalization remains unresolved; this describes our state of knowledge.

Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR. 1995. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: Inhibition by overexpression of Bcl-2 and Abl. J Exp Med 182: 1545–1556.
An early paper describing the use of annexin V to detect apoptosis.

Phagocyte Receptors for Dying Cells

Wu YC, Horvitz HR. 1998. The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93: 951–960.
The original characterization of CED7.

Hamon Y, Broccardo C, Chambenoit O, Luciani MF, Toti F, Chaslin S, Freyssinet JM, Devaux PF, McNeish J, Marguet D, et al. 2000. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nat Cell Biol 2: 399–406.
ABC1 in mammalian engulfment of dying cells and its possible role in phospholipid scrambling; the relationship to caspases remains unclear.

Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL, Earp HS, Matsushima GK. 2001. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411: 207–211.

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. 2002. Identification of a factor that links apoptotic cells to phagocytes. Nature 417: 182–187.
The identification of MFG-E8 as a bridge molecule recognizing phosphatidylserine and its role in engulfment of dying cells.

Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S. 2007. Identification of Tim4 as a phosphatidylserine receptor. Nature 450: 435–439.

Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS. 2007. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/DOCK180/ RAC module. Nature 450: 430–434.

Franc NC, Heitzler P, Ezekowitz RA, White K. 1999. Requirement for croquemort in phagocytosis of apoptotic cells in Drosophila. Science 284: 1991–1994.

Eat-me Signals and Engulfment

Reddien PW, Horvitz HR. 2004. The engulfment process of programmed cell death in Caenorhabditis elegans. Annu Rev Cell Dev Biol 20: 193–221.
A detailed review of the engulfment process in nematodes.

Park SY, Kang KB, Thapa N, Kim SY, Lee SJ, Kim IS. 2008. Requirement of adaptor protein GULP during stabilin-2-mediated cell corpse engulfment. J Biol Chem 283: 10593–10600.

Kinchen JM, Ravichandran KS. 2010. Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature 464: 778–782.
Two additional genes involved in engulfment of dying cells. Although not discussed in this chapter, the findings are of interest.

Waste Management

Kiss RS, Elliott MR, Ma Z, Marcel YL, KS Ravichandran. 2006. Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes. Curr Biol 16: 2252–2258.

A-Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Diaz M, Gallardo G, et al. 2009. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31: 245–258.
In addition to illustrating the role of LXR in clearance of dying cells, this paper shows that activation of LXR may suppress disease consequences that arise due to defective apoptosis.

Dying Cells and Innate Immunity

Rock KL, Latz E, Ontiveros F, Kono H. 2010. The sterile inflammatory response. Annu Rev Immunol 28: 321–342.

Birge RB, Ucker DS. 2008. Innate apoptotic immunity: The calming touch of death. Cell Death Differ 15: 1096–1102.

Dying Cells and Adaptive Immunity

Green DR, Ferguson T, Zitvogel L, Kroemer G. 2009. Immunogenic and tolerogenic cell death. Nat Rev Immunol 9: 353–363.
A survey of the effects of dying cells on the adaptive immune system.

Gaipl US, Munoz LE, Grossmayer G, Lauber K, Franz S, Sarter K, Voll RE, Winkler T, Kuhn A, Kalden J, et al. 2007. Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun 28: 114–121.
An overview of the possible role of engulfment defects in autoimmune disease.

Bianchi ME 2007. DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol 81: 1–5.
Peng Y, Martin DA, Kenkel J, Zhang K, Ogden CA, Elkon KB. 2007. Innate and adaptive immune response to apoptotic cells. J Autoimmun 29: 303–309.

Matzinger P. 1994. Tolerance, danger, and the extended family. Annu Rev Immunol 12: 991–1045.
The original review that triggered the idea that dying cells influence the adaptive immune response.

Skoberne M, Beignon AS, Larsson M, Bhardwaj N. 2005. Apoptotic cells at the crossroads of tolerance and immunity. Curr Top Microbiol Immunol 289: 259–292.

Compensatory Proliferation

Fan Y, Bergmann A. 2008. Apoptosis-induced compensatory proliferation. The cell is dead. Long live the cell! Trends Cell Biol 18: 467–473.

Ryoo HD, Gorenc T, Steller H. 2004. Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev Cell 7: 491–501.
Two pathways involved in compensatory proliferation in flies.

Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, CY Li. 2010. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci Signal 3: ra13.
A possible mechanism of compensatory proliferation in response to apoptosis in mammals.

CHAPTER 10
Conradt B. 2009. Genetic control of programmed cell death during animal development. Annu Rev Genet 43: 493–523.

Baehrecke EH. 2002. How death shapes life during development. Nat Rev Mol Cell Biol 3: 779–787.
Meier P, Finch A, Evan G. 2000. Apoptosis in development. Nature 407: 796–801.

Cell Death in Nematode Development

Ellis RE, Yuan JY, Horvitz HR. 1991. Mechanisms and functions of cell death. Annu Rev Cell Biol 7: 663–698.
An early survey of cell death in nematode development.

Ellis HM, Horvitz HR. 1986. Genetic control of programmed cell death in the nematode C. elegans. Cell 44: 817–829.
The original paper defining the genetic basis for cell death in nematode development.

Maurer CW, Chiorazzi M, Shaham S. 2007. Timing of the onset of a developmental cell death is controlled by transcriptional induction of the C. elegans ced-3 caspase-encoding gene. Development 134: 1357–1368.

Abraham MC, Lu Y, Shaham S. 2007. A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans. Dev Cell 12: 73–86.
Cell death in the tail-spike cell.

Ellis RE, Horvitz HR. 1991. Two C. elegans genes control the programmed deaths of specific cells in the pharynx. Development 112: 591-603.
The identification of CES1 and CES2 in specifying cell death in nematode development.

Metzstein MM, Hengartner MO, Tsung N, Ellis RE, Horvitz HR. 1996. Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2. Nature 382: 545–547.

Zarkower D, Hodgkin J. 1992. Molecular analysis of the C. elegans sex-determining gene tra-1: A gene encoding two zinc finger proteins. Cell 70: 237–249.

Cell Death in Fly Development

Hay BA, Guo M. 2006. Caspase-dependent cell death in Drosophila. Annu Rev Cell Dev Biol 22: 623–650.

Baehrecke EH. 2000. Steroid regulation of programmed cell death during Drosophila development. Cell Death Differ 7: 1057–1062.

Rusconi JC, Hays R, Cagan RL. 2000. Programmed cell death and patterning in Drosophila. Cell Death Differ 7: 1063–1070.

Berry DL, Baehrecke EH. 2007. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131: 1137–1148.
The first clear-cut description of autophagy-dependent cell death in development.

Denton D, Shravage B, Simin R, Mills K, Berry DL, Baehrecke EH, Kumar S. 2009. Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Curr Biol 19: 1741–1746.
Another example of developmental cell death dependent on autophagy.

Cell Death in Vertebrate Development

Montero JA, Hurlé JM. 2010. Sculpturing digit shape by cell death. Apoptosis 15: 365–375.

Coucouvanis E, Martin GR. 1995. Signals for death and survival: A two-step mechanism for cavitation in the vertebrate embryo. Cell 83: 279–287.

Ishizuya-Oka A, Hasebe T, Shi YB. 2010. Apoptosis in amphibian organs during metamorphosis. Apoptosis 15: 350–364.

Cell Death and Selection

Yuen EC, Howe CL, Li Y, Holtzman DM, Mobley WC. 1996. Nerve growth factor and the neurotrophic factor hypothesis. Brain Dev 18: 362–368.

O’Leary DD, Fawcett JW, Cowan WM. 1986. Topographic targeting errors in the retinocollicular projection and their elimination by selective ganglion cell death. J Neurosci 6: 3692–3705.
An example of how cell death can select for proper neuronal connections.

Palmer E. 2003. Negative selection—Clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol 3: 383–391.

Strasser A, Puthalakath H, O’Reilly LA, Bouillet P. 2008. What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol 86: 57–66.

Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM, Strasser A. 2002. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415: 922–926.
The role of BIM in the negative selection of immature T cells.

CHAPTER 11

Cancer and Apoptosis

Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100: 57–70.
An influential overview of how cancer occurs, including the role of apoptosis evasion.

Green DR, Evan GI. 2002. A matter of life and death. Cancer Cell 1: 19–30.
A proposal that cancer is a largely a consequence of unregulated proliferation combined with evasion of apoptosis.

Letai AG. 2008. Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer 8: 121–132.
Harnessing our knowledge of cell death in treating cancer.

Pelengaris S, Khan M, Evan GI. 2002. Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109: 321–334.
An important paper that illustrates the requirements of c-Myc–induced cancer.

p53

Junttila MR, Evan GI. 2009. p53—A Jack of all trades but master of none. Nat Rev Cancer 9: 821–829.

Vousden KH, Prives C. 2009. Blinded by the light: The growing complexity of p53. Cell 137: 413–431.

Vousden KH, Lane DP. 2007. p53 in health and disease. Nat Rev Mol Cell Biol 8: 275–283.

Caspari T. 2000. How to activate p53. Curr Biol 10: R315–R317.

Sherr CJ. 2006. Divorcing ARF and p53: An unsettled case. Nat Rev Cancer 6: 663–673.
A discussion of the functions of ARF in p53 activation and other possible roles.

Murray-Zmijewski F, Slee EA, Lu X. 2008. A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9: 702–712.

Oren M, Levine AJ. 1983. Molecular cloning of a cDNA specific for the murine p53 cellular tumor antigen. Proc Natl Acad Sci 80: 56–59.
One of two early papers describing a role for p53 in cancer.

Lane DP. 1984. Cell immortalization and transformation by the p53 gene. Nature 312: 596–597.
See above. Interestingly, the p53 cloned was a dominant-negative mutant that promoted (rather than suppressed) cellular transformation.

p53 and Apoptosis

Yu J, Zhang L. 2008. PUMA, a potent killer with or without p53. Oncogene (suppl 1) 27: S71–S83.
A review covering the roles for PUMA as a mediator of p53-induced apoptosis.

Green DR, Kroemer G. 2009. Cytoplasmic functions of the tumour suppressor p53. Nature 458: 1127–1130.

Tumor Suppression

Lowe SW, Cepero E, Evan G. 2004. Intrinsic tumour suppression. Nature 432: 307–315.
Christophorou MA, Ringshausen I, Finch AJ, Swigart LB, Evan GI. 2006. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443: 214–217.
An exploration of how p53 suppresses oncogenesis.

Campisi J. 2005. Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors. Cell 120: 513–522.
An overview of tumor suppression, beyond apoptosis.

Autophagy and Cancer

White E, Karp C, Strohecker AM, Guo Y, Mathew R. 2010. Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol 22: 212–217.

Mathew R, Karantza-Wadsworth V, White E. 2007. Role of autophagy in cancer. Nat Rev Cancer 7: 961–967.

Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, et al. 2006. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10: 51–64.
Evidence that autophagy acts as a tumor suppressor.
Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. 2008. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest 118: 79–88.
Induction of autophagic cell death by chloroquine, applied to cancer therapy.

CHAPTER 12

Modeling Apoptosis

Aldridge BB, Burke JM, Lauffenburger DA, Sorger PK. 2006. Physicochemical modelling of cell signalling pathways. Nat Cell Biol 8: 1195–1203.

Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK. 2009. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459: 428–432.
Evidence of stochastic processes in apoptosis.

Pomerening JR. 2008. Uncovering mechanisms of bistability in biological systems. Curr Opin Biotechnol 19: 381–388.
An introduction to bistability.

Cui J, Chen C., Lu H, Sun T, Shen P. 2008. Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch. PLoS One 3: e1469.
This and the following paper model BCL-2 family interactions in apoptosis.

Sun T, Lin X, Wei Y, Xu Y, Shen P. 2010. Evaluating bistability of Bax activation switch. FEBS Lett 584: 954–960.
See above.

Legewie S, Bluthgen N, Herzel H. 2006. Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability. PLoS Comput Biol 2: e120.

Making Cells Die

Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM. 2005. An inducible caspase 9 safety switch for T-cell therapy. Blood 105: 4247–4254.
One way of triggering apoptosis, on demand.

Chonghaile TN, Letai A. 2008. Mimicking the BH3 domain to kill cancer cells. Oncogene (suppl 1) 27: S149–S157.
A survey of BCL-2 inhibitors, including ABT-737, and how they work.

Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, et al. 2005. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681.
The first description of ABT-737 and how it was discovered.

Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. 2009. Awakening guardian angels: Drugging the p53 pathway. Nat Rev Cancer 9: 862–873.

Making Cells Live
Enari M, Hug H, Nagata S. 1995. Involvement of an ICE-like protease in Fas-mediated apoptosis. Nature 375: 78–81.
The first description of the protective effect of caspase (called “ICE-like protease) inhibitors in protection from liver destruction induced by injection of antibodies to CD95 (called “Fas”).

Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, et al. 2008. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4: 313–321.

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The Button Experiment
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The first description of the button experiment, a simple idea with intriguing consequences.

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An introduction to an extensive online survey of many different proteins that have been described to impact on the mitochondrial pathway of apoptosis.

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