Stress Induced Mutagenesis, Genetic Diversification, and Cell Survival via Anastasis, the Reversal of Late Stage Apoptosis

  • Ho Lam Tang
  • Ho Man Tang
  • Denise J. Montell


Changes in genomic DNA are critical for evolution as they generate genetic diversity, which is the substrate for natural selection. However, most mutations are deleterious, so protective mechanisms have evolved such as apoptotic cell death, to eliminate damaged cells. Apoptosis is generally assumed to be irreversible once massive destruction of structural and functional cellular components occurs. Recent surprising studies reveal that dying cells can reverse the apoptotic process, survive, and proliferate, even after sustaining DNA damage. This process has been named anastasis. While most cells repair their damaged DNA, residual genetic alterations persist in some cells and can result in oncogenic transformation. Although proliferation of transformed cells is a negative consequence, anastasis may serve useful purposes as well. For example, such a cell survival mechanism could serve to salvage postmitotic cells, which are difficult to replace, and thereby limit permanent tissue damage due to transient stresses. The DNA mutations that persist following anastasis represent a form of stress-induced mutagenesis, increasing genetic and phenotypic diversity in response to environmental or physiological stresses that initiate apoptosis. Negative side effects of this otherwise beneficial process may include carcinogenesis and evolution of drug resistance following chemotherapy.


Annexin Versus Caspase Cascade Membrane Blebbing Nuclear Condensation Mitochondrial Fragmentation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abraham MC, Lu Y, Shaham S (2007) A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans. Dev Cell 12:73–86PubMedCrossRefGoogle Scholar
  2. Abrams JM, White K, Fessler LI, Steller H (1993) Programmed cell death during Drosophila embryogenesis. Development 117:29–43PubMedGoogle Scholar
  3. Aitken RJ, Findlay JK, Hutt KJ, Kerr JB (2011) Apoptosis in the germ line. Reproduction 141:139–150PubMedCrossRefGoogle Scholar
  4. Arama E, Agapite J, Steller H (2003) Caspase activity and a specific cytochrome C are required for sperm differentiation in Drosophila. Dev Cell 4:687–697PubMedCrossRefGoogle Scholar
  5. Baehrecke EH (2002) How death shapes life during development. Nat Rev Mol Cell Biol 3:779–787PubMedCrossRefGoogle Scholar
  6. Bergmann A, Steller H (2010) Apoptosis, stem cells, and tissue regeneration. Sci Signal 3:re8PubMedCrossRefGoogle Scholar
  7. Betti CJ, Villalobos MJ, Diaz MO, Vaughan AT (2001) Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system. Cancer Res 61:4550–4555PubMedGoogle Scholar
  8. Blum ES, Abraham MC, Yoshimura S, Lu Y, Shaham S (2012) Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335:970–973PubMedCrossRefGoogle Scholar
  9. Bouvard V, Zaitchouk T, Vacher M, Duthu A, Canivet M, Choisy-Rossi C, Nieruchalski M, May E (2000) Tissue and cell-specific expression of the p53-target genes: bax, fas, mdm2 and waf1/p21, before and following ionising irradiation in mice. Oncogene 19:649–660PubMedCrossRefGoogle Scholar
  10. Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5:231–237PubMedCrossRefGoogle Scholar
  11. Bruey JM, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, Gurbuxani S, Arrigo AP, Kroemer G, Solary E et al (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2:645–652PubMedCrossRefGoogle Scholar
  12. Buttner S, Eisenberg T, Herker E, Carmona-Gutierrez D, Kroemer G, Madeo F (2006) Why yeast cells can undergo apoptosis: death in times of peace, love, and war. J Cell Biol 175:521–525PubMedCrossRefGoogle Scholar
  13. Byrne HM (2010) Dissecting cancer through mathematics: from the cell to the animal model. Nat Rev Cancer 10:221–230PubMedCrossRefGoogle Scholar
  14. Carmona-Gutierrez D, Eisenberg T, Buttner S, Meisinger C, Kroemer G, Madeo F (2010) Apoptosis in yeast: triggers, pathways, subroutines. Cell Death Differ 17:763–773PubMedCrossRefGoogle Scholar
  15. Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y (2000) Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406:855–862PubMedCrossRefGoogle Scholar
  16. Chen Y, Klionsky DJ (2011) The regulation of autophagy—unanswered questions. J Cell Sci 124:161–170PubMedCrossRefGoogle Scholar
  17. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010) The BCL-2 family reunion. Mol Cell 37:299–310PubMedCrossRefGoogle Scholar
  18. Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12(Suppl 2):1509–1518PubMedCrossRefGoogle Scholar
  19. Dandel M, Weng Y, Siniawski H, Stepanenko A, Krabatsch T, Potapov E, Lehmkuhl HB, Knosalla C, Hetzer R (2011) Heart failure reversal by ventricular unloading in patients with chronic cardiomyopathy: criteria for weaning from ventricular assist devices. Eur Heart J 32: 1148–1160PubMedCrossRefGoogle Scholar
  20. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedCrossRefGoogle Scholar
  21. de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, LeMeur M et al (1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94:7303–7307PubMedCrossRefGoogle Scholar
  22. Demirozu ZT, Frazier OH (2012) Remission of chronic, advanced heart failure after left ventricular unloading with an implantable left ventricular assist device. Tex Heart Inst J 39:268–270PubMedGoogle Scholar
  23. Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388:300–304PubMedCrossRefGoogle Scholar
  24. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17:2215–2223PubMedCrossRefGoogle Scholar
  25. Ditzel M, Broemer M, Tenev T, Bolduc C, Lee TV, Rigbolt KT, Elliott R, Zvelebil M, Blagoev B, Bergmann A et al (2008) Inactivation of effector caspases through nondegradative polyubiquitylation. Mol Cell 32:540–553PubMedCrossRefGoogle Scholar
  26. Dlugosz PJ, Billen LP, Annis MG, Zhu W, Zhang Z, Lin J, Leber B, Andrews DW (2006) Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J 25:2287–2296PubMedCrossRefGoogle Scholar
  27. Drummond-Barbosa D, Spradling AC (2001) Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev Biol 231:265–278PubMedCrossRefGoogle Scholar
  28. 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 102:33–42PubMedCrossRefGoogle Scholar
  29. Eguchi-Ishimae M, Eguchi M, Ishii E, Miyazaki S, Ueda K, Kamada N, Mizutani S (2001) Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals. Blood 97:737–743PubMedCrossRefGoogle Scholar
  30. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50PubMedCrossRefGoogle Scholar
  31. Flanagan L, Sebastia J, Tuffy LP, Spring A, Lichawska A, Devocelle M, Prehn JH, Rehm M (2010) XIAP impairs Smac release from the mitochondria during apoptosis. Cell Death Dis 1:e49PubMedCrossRefGoogle Scholar
  32. Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375PubMedCrossRefGoogle Scholar
  33. Fu D, Calvo JA, Samson LD (2012) Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 12:104–120PubMedGoogle Scholar
  34. Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147:742–758PubMedCrossRefGoogle Scholar
  35. Fullwood MJ, Lee J, Lin L, Li G, Huss M, Ng P, Sung WK, Shenolikar S (2011) Next-generation sequencing of apoptotic DNA breakpoints reveals association with actively transcribed genes and gene translocations. PLoS One 6:e26054PubMedCrossRefGoogle Scholar
  36. Gabai VL, Mabuchi K, Mosser DD, Sherman MY (2002) Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 22:3415–3424PubMedCrossRefGoogle Scholar
  37. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S et al (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120PubMedCrossRefGoogle Scholar
  38. Geske FJ, Lieberman R, Strange R, Gerschenson LE (2001) Early stages of p53-induced apoptosis are reversible. Cell Death Differ 8:182–191PubMedCrossRefGoogle Scholar
  39. Glücksmann A (1951) Cell deaths in normal vertebrate ontogeny. Biol Rev Camb Philos Soc 26:59–86CrossRefGoogle Scholar
  40. 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: 156–162PubMedCrossRefGoogle Scholar
  41. Goldstein JC, Munoz-Pinedo C, Ricci JE, Adams SR, Kelekar A, Schuler M, Tsien RY, Green DR (2005) Cytochrome c is released in a single step during apoptosis. Cell Death Differ 12:453–462PubMedCrossRefGoogle Scholar
  42. Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 32:37–43PubMedCrossRefGoogle Scholar
  43. Gordon WC, Casey DM, Lukiw WJ, Bazan NG (2002) DNA damage and repair in light-induced photoreceptor degeneration. Invest Ophthalmol Vis Sci 43:3511–3521PubMedGoogle Scholar
  44. Gourlay CW, Du W, Ayscough KR (2006) Apoptosis in yeast—mechanisms and benefits to a unicellular organism. Mol Microbiol 62:1515–1521PubMedCrossRefGoogle Scholar
  45. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629PubMedCrossRefGoogle Scholar
  46. Haider N, Narula N, Narula J (2002) Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling. J Card Fail 8:S512–S517PubMedCrossRefGoogle Scholar
  47. Hammill AK, Uhr JW, Scheuermann RH (1999) Annexin V staining due to loss of membrane asymmetry can be reversible and precede commitment to apoptotic death. Exp Cell Res 251:16–21PubMedCrossRefGoogle Scholar
  48. Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB (2001) Characterization of XIAP-­deficient mice. Mol Cell Biol 21:3604–3608PubMedCrossRefGoogle Scholar
  49. Horvitz HR (1999) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res 59:1701s–1706sPubMedGoogle Scholar
  50. Jacobson MD, Weil M, Raff MC (1997) Programmed cell death in animal development. Cell 88:347–354PubMedCrossRefGoogle Scholar
  51. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164PubMedCrossRefGoogle Scholar
  52. Juo P, Kuo CJ, Yuan J, Blenis J (1998) Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol 8:1001–1008PubMedCrossRefGoogle Scholar
  53. Kenis H, Zandbergen HR, Hofstra L, Petrov AD, Dumont EA, Blankenberg FD, Haider N, Bitsch N, Gijbels M, Verjans JW et al (2010) Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imaging. J Nucl Med 51:259–267PubMedCrossRefGoogle Scholar
  54. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-­ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedCrossRefGoogle Scholar
  55. Kroemer G, Martin SJ (2005) Caspase-independent cell death. Nat Med 11:725–730PubMedCrossRefGoogle Scholar
  56. 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 384:368–372PubMedCrossRefGoogle Scholar
  57. 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 111:331–342PubMedCrossRefGoogle Scholar
  58. Lam E (2004) Controlled cell death, plant survival and development. Nat Rev Mol Cell Biol 5:305–315PubMedCrossRefGoogle Scholar
  59. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346–347PubMedCrossRefGoogle Scholar
  60. Lettre G, Hengartner MO (2006) Developmental apoptosis in C. elegans: a complex CEDnario. Nat Rev Mol Cell Biol 7:97–108PubMedCrossRefGoogle Scholar
  61. 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 94:491–501PubMedCrossRefGoogle Scholar
  62. Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99PubMedCrossRefGoogle Scholar
  63. Liu X, Zou H, Slaughter C, Wang X (1997) DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89:175–184PubMedCrossRefGoogle Scholar
  64. Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408:1004–1008PubMedCrossRefGoogle Scholar
  65. Lockshin RA, Williams CM (1964) Programmed cell death. II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J Insect Physiol 10:643–649CrossRefGoogle Scholar
  66. Logue SE, Elgendy M, Martin SJ (2009) Expression, purification and use of recombinant annexin V for the detection of apoptotic cells. Nat Protoc 4:1383–1395PubMedCrossRefGoogle Scholar
  67. 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 94:481–490PubMedCrossRefGoogle Scholar
  68. Luthi AU, Martin SJ (2007) The CASBAH: a searchable database of caspase substrates. Cell Death Differ 14:641–650PubMedCrossRefGoogle Scholar
  69. MacFarlane M, Merrison W, Bratton SB, Cohen GM (2002) Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J Biol Chem 277: 36611–36616PubMedCrossRefGoogle Scholar
  70. Marine JC, Lozano G (2010) Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 17:93–102PubMedCrossRefGoogle Scholar
  71. Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–129PubMedCrossRefGoogle Scholar
  72. Maxmen A (2012) Malaria surge feared. Nature 485:293PubMedCrossRefGoogle Scholar
  73. McKechnie NM, Foulds WS (1980) Recovery of the rabbit retina after light damage (preliminary observations). Albrecht Von Graefes Arch Klin Exp Ophthalmol 212:271–283PubMedGoogle Scholar
  74. Milligan SC, Alb JG Jr, Elagina RB, Bankaitis VA, Hyde DR (1997) The phosphatidylinositol transfer protein domain of Drosophila retinal degeneration B protein is essential for photoreceptor cell survival and recovery from light stimulation. J Cell Biol 139:351–363PubMedCrossRefGoogle Scholar
  75. Milting H, Bartling B, Schumann H, El-Banayosy A, Wlost S, Ruter F, Darmer D, Holtz J, Korfer R, Zerkowski HR (1999) Altered levels of mRNA of apoptosis-mediating genes after mid-term mechanical ventricular support in dilative cardiomyopathy—first results of the Halle Assist Induced Recovery Study (HAIR). Thorac Cardiovasc Surg 47:48–50PubMedCrossRefGoogle Scholar
  76. Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69: 1237–1245PubMedCrossRefGoogle Scholar
  77. Mrozek A, Petrowsky H, Sturm I, Kraus J, Hermann S, Hauptmann S, Lorenz M, Dorken B, Daniel PT (2003) Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability. Cell Death Differ 10:461–467PubMedCrossRefGoogle Scholar
  78. Murray-Zmijewski F, Slee EA, Lu X (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9:702–712PubMedCrossRefGoogle Scholar
  79. Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD, Dal Bello B, Semigran MJ, Bielsa-Masdeu A, Dec GW et al (1999) Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 96:8144–8149PubMedCrossRefGoogle Scholar
  80. Narula J, Haider N, Arbustini E, Chandrashekhar Y (2006) Mechanisms of disease: apoptosis in heart failure—seeing hope in death. Nat Clin Pract Cardiovasc Med 3:681–688PubMedCrossRefGoogle Scholar
  81. Pandey P, Saleh A, Nakazawa A, Kumar S, Srinivasula SM, Kumar V, Weichselbaum R, Nalin C, Alnemri ES, Kufe D et al (2000) Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 19:4310–4322PubMedCrossRefGoogle Scholar
  82. Paul C, Manero F, Gonin S, Kretz-Remy C, Virot S, Arrigo AP (2002) Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol 22:816–834PubMedCrossRefGoogle Scholar
  83. Peng J, Tan C, Roberts GJ, Nikolaeva O, Zhang Z, Lapolla SM, Primorac S, Andrews DW, Lin J (2006) tBid elicits a conformational alteration in membrane-bound Bcl-2 such that it inhibits Bax pore formation. J Biol Chem 281:35802–35811PubMedCrossRefGoogle Scholar
  84. Perez-Crespo M, Pintado B, Gutierrez-Adan A (2008) Scrotal heat stress effects on sperm viability, sperm DNA integrity, and the offspring sex ratio in mice. Mol Reprod Dev 75:40–47PubMedCrossRefGoogle Scholar
  85. Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jaattela M, Penninger JM, Garrido C et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843PubMedCrossRefGoogle Scholar
  86. Reed JC, Paternostro G (1999) Postmitochondrial regulation of apoptosis during heart failure. Proc Natl Acad Sci USA 96:7614–7616PubMedCrossRefGoogle Scholar
  87. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897–907PubMedCrossRefGoogle Scholar
  88. Rosenberg SM (2001) Evolving responsively: adaptive mutation. Nat Rev Genet 2:504–515PubMedCrossRefGoogle Scholar
  89. Ross GM (1999) Induction of cell death by radiotherapy. Endocr Relat Cancer 6:41–44PubMedCrossRefGoogle Scholar
  90. Salinas LS, Maldonado E, Navarro RE (2006) Stress-induced germ cell apoptosis by a p53 ­independent pathway in Caenorhabditis elegans. Cell Death Differ 13:2129–2139PubMedCrossRefGoogle Scholar
  91. Schug ZT, Gonzalvez F, Houtkooper RH, Vaz FM, Gottlieb E (2011) BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ 18:538–548PubMedCrossRefGoogle Scholar
  92. Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS (2005) XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J 24:645–655PubMedCrossRefGoogle Scholar
  93. Sheridan C, Martin SJ (2008) Commitment in apoptosis: slightly dead but mostly alive. Trends Cell Biol 18:353–357PubMedCrossRefGoogle Scholar
  94. Stanulla M, Wang J, Chervinsky DS, Thandla S, Aplan PD (1997) DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. Mol Cell Biol 17:4070–4079PubMedGoogle Scholar
  95. Stennicke HR, Jurgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D et al (1998) Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem 273:27084–27090PubMedCrossRefGoogle Scholar
  96. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724PubMedCrossRefGoogle Scholar
  97. 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 397:441–446PubMedCrossRefGoogle Scholar
  98. Suzuki Y, Nakabayashi Y, Takahashi R (2001) Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-­apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 98:8662–8667PubMedCrossRefGoogle Scholar
  99. Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632PubMedCrossRefGoogle Scholar
  100. Takemoto K, Nagai T, Miyawaki A, Miura M (2003) Spatio-temporal activation of caspase revealed by indicator that is insensitive to environmental effects. J Cell Biol 160:235–243PubMedCrossRefGoogle Scholar
  101. Tang HL, Yuen KL, Tang HM, Fung MC (2009) Reversibility of apoptosis in cancer cells. Br J Cancer 100:118–122PubMedCrossRefGoogle Scholar
  102. Tang HL, Tang HM, Mak KH, Hu S, Wang SS, Wong KM, Wong CS, Wu HY, Law HT, Liu K et al (2012) Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol Biol Cell 23:2240–2252PubMedCrossRefGoogle Scholar
  103. Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241PubMedCrossRefGoogle Scholar
  104. Tubio JM, Estivill X (2011) Cancer: when catastrophe strikes a cell. Nature 470:476–477PubMedCrossRefGoogle Scholar
  105. Tyas L, Brophy VA, Pope A, Rivett AJ, Tavare JM (2000) Rapid caspase-3 activation during ­apoptosis revealed using fluorescence-resonance energy transfer. EMBO Rep 1:266–270PubMedCrossRefGoogle Scholar
  106. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714PubMedCrossRefGoogle Scholar
  107. Vaughan AT, Betti CJ, Villalobos MJ (2002) Surviving apoptosis. Apoptosis 7:173–177PubMedCrossRefGoogle Scholar
  108. Vazquez A, Bond EE, Levine AJ, Bond GL (2008) The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 7:979–987PubMedCrossRefGoogle Scholar
  109. 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 102:43–53PubMedCrossRefGoogle Scholar
  110. Wang X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15:2922–2933PubMedGoogle Scholar
  111. Wang ZQ, Stingl L, Morrison C, Jantsch M, Los M, Schulze-Osthoff K, Wagner EF (1997) PARP is important for genomic stability but dispensable in apoptosis. Genes Dev 11:2347–2358PubMedCrossRefGoogle Scholar
  112. Wang L, Du F, Wang X (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133:693–703PubMedCrossRefGoogle Scholar
  113. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071PubMedGoogle Scholar
  114. Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature 408:1008–1012PubMedCrossRefGoogle Scholar
  115. 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 275:1129–1132PubMedCrossRefGoogle Scholar
  116. Yin XM, Oltvai ZN, Korsmeyer SJ (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369:321–323PubMedCrossRefGoogle Scholar
  117. Zelent A, Greaves M, Enver T (2004) Role of the TEL-AML1 fusion gene in the molecular ­pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene 23:4275–4283PubMedCrossRefGoogle Scholar
  118. Zhu Y, Yang GY, Ahlemeyer B, Pang L, Che XM, Culmsee C, Klumpp S, Krieglstein J (2002) Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci 22:3898–3909PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ho Lam Tang
    • 1
  • Ho Man Tang
    • 1
  • Denise J. Montell
    • 1
  1. 1.Department of Biological Chemistry, Center for Cell DynamicsJohns Hopkins University School of MedicineBaltimoreUSA

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