Programmed Nuclear Death and Other Apoptotic-Like Phenomena in Ciliated Protozoa

  • Ana Martín González
  • Silvia Díaz
  • Andrea Gallego
  • Juan C. Gutiérrez
Part of the Molecular Biology Intelligence Unit book series (MBIU)


One of the more usual hallmarks of programmed cell death (PCD) in multicellular organisms is the nuclear chromatin condensation and the DNA fragmentation in multiple oligonucleosome length fragments. In Tetrahymena thermophila and other free-living ciliated protozoa, a controlled nuclear degradation process develops during conjugation, the sexual phase of the life cycle, which includes DNA condensation and later degradation, with or without previous nuclear fragmentation. The main objective of this programmed nuclear death (PND) is to remove the old macronucleus whereas a new recombinant vegetative nucleus is developing in each conjugating cell. Alternatively, in other ciliates, mainly inhabitants of terrestrial ecosystems, which have not conjugation, PND is restricted to encystment, a cellular differentiation process induced by different environmental stressors, mainly starvation, the same inducer of conjugation. The mechanism of PND is still not elucidated, but we know that it involves caspase-like proteins, an intense acid phosphatase activity and an autophagic process. Also, several reports indicate the existence of mitochondrial participation in macronuclear degradation. After analysing the updated information relative to programmed nuclear death in ciliated protozoa, we conclude that these eukaryotic microorganisms represent an alternative and good option to study the PCD process in unicellular organisms. The recently completed macronuclear genome sequencing in the model ciliate T. thermophila, provides insights to analyze and understand the molecular mechanisms of PCD in ciliates and, likewise, it will give rise to useful information about the origin and evolution of cell death in biological systems.


Chromatin Condensation Cell Death Differ Ciliated Protozoan Eukaryotic Microorganism Zygotic Nucleus 
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.


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  1. 1.
    Lee JJ, Leedale GF, Bradbury P, eds. Illustrated Guide to the Protozoa. 2nd ed. Blackwell Publishing, 2005.Google Scholar
  2. 2.
    Fenchel T. Ecology of Protozoa. 2nd ed. Madison: Science Tech, 1987.Google Scholar
  3. 3.
    Paulin JJ, Morphology and cytology of ciliates. In: Hausmann K, Bradbury PC, eds. Ciliates. Cells as organisms. Stuttgart: Gustav Fischer, 1996:1–40.Google Scholar
  4. 4.
    Hausmann K, Hülsmann N, Radek R. Protistology. 3rd ed. Berlin: Schweizerbart’sche Verlagbuchhandlung, 2003.Google Scholar
  5. 5.
    Radek R, Hausmann K. Phagotrophy in ciliates. In: Hausmann K, Bradbury PC, eds. Ciliates. Cells as organisms. Stuttgart: Gustav Fisher, 1996:197–219.Google Scholar
  6. 6.
    Prescott DM. The DNA of ciliated Protozoa. Microbiol Rev 1994; 58:233–266.PubMedGoogle Scholar
  7. 7.
    Prescott DM. Evolution of DNA organization in hypotrichous ciliates. Ann NY Acad Sci 1999; 870:301–313.PubMedCrossRefGoogle Scholar
  8. 8.
    Raikov IB. The Protozoan Nucleus. Morphology and Evolution. Wien: Springer-Verlag, 1982.Google Scholar
  9. 9.
    Raikov IB. Nuclei of ciliates. In: Hausmann K, Bradbury PC, eds. Ciliates. Cells as organisms. Stuttgart: Gustav Fisher, 1996:221–242.Google Scholar
  10. 10.
    Gutiérrez JC, Martín-González A, Matsusaka T. Towards a generalized model of encystment (cryptobiosis) in ciliates: a review and a hypothesis. BioSystems 1990; 24:17–24.PubMedCrossRefGoogle Scholar
  11. 11.
    Gutiérrez JC, Díaz S Ortega R et al. Ciliate resting cyst wall: a comparative review. Recent Res Develop Microbiol 2003; 7:361–379.Google Scholar
  12. 12.
    Gutiérrez JC, Izquierdo A, Martín-González A et al. Cryptobiosis in colpodid ciliates: A microbial eukaryotic differentiation model. Recent Res Devel Microbiol 1998; 2:1–15.Google Scholar
  13. 13.
    Gutiérrez JC, Callejas S, Borniquel S et al. Ciliate cryptobiosis: a microbial strategy against environmental starvation. Int Microbiol 2001; 4:151–157.PubMedGoogle Scholar
  14. 14.
    Martín-González A, Benítez L, Gutiérrez JC. Ultrastructural analisis of resting cysts and encystment in Colopoda inflata. 2. Encystment process and a review of ciliate resting cyst classification. Cytobios 1992b; 72:93–103.Google Scholar
  15. 15.
    Miyake A. Physiology and biochemistry of conjugation in ciliates. In: Levandowsky M, Hutner SH, eds. Biochemistry and Physiology of Protozoa. New York: Academic Press, 1981; 121–198.Google Scholar
  16. 16.
    Watanabe T. The role of ciliary surfaces in mating in Paramecium. In: Bloodgood RA, eds. Ciliary and Flagellar Membranes. New York: Plenum Press, 1990:149–171.Google Scholar
  17. 17.
    Miyake A. Fertilization and sexuality in ciliates. In: Hausmann K, Bradbury PC, eds. Ciliates. Cells as organisms. Stuttgart: Gustay Fisher, 1996:243–290.Google Scholar
  18. 18.
    Collins K, Gorovsky MA. Tetrahymena thermophila. Curr Biol 2005; 10:R317–318.CrossRefGoogle Scholar
  19. 19.
    Turkewitz AP, Orias E, Kapler G. Functional genomics: the coming of age for Tetrahymena thermophila. Trends in genetics 2002; 18:35–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Martindale DW, Allis CD, Bruns PJ. Conjugation in Tetrahymena thermophila. A temporal analysis of cytological stages. Exp Cell Res 1992; 140:227–236.CrossRefGoogle Scholar
  21. 21.
    Orias E. Ciliate conjugation. In: Gall JG ed. The Molecular Biology of Ciliated Protozoa. Academic Press, 1986:45–84.Google Scholar
  22. 22.
    Davis MC, Wart JG, Herrick G et al. Programmed nuclear death: Apoptotic-like degradation of specific nuclei in conjugating Tetrahymena. Dev Biol 1992; 154:419–442.PubMedCrossRefGoogle Scholar
  23. 23.
    Weiske-Benner A, Eckert WA. Differentiation of nuclear structure during the sexual cycle in Tetrahymena thermophila; II. Degeneration and autolysis of macro-and micronuclei. Differentiation 1987; 34:1–12.CrossRefGoogle Scholar
  24. 24.
    Lockshin RA, Zaheri Z. Apoptosis, autophagy and more. Int J Biochem Cell Biol 2004; 36:2405–2419.PubMedCrossRefGoogle Scholar
  25. 25.
    Walker PR, Sikorska M. New aspects of the mechanism of DNA fragmentation in apoptosis. Biochem Cell Biol 1997;75:287–299.PubMedCrossRefGoogle Scholar
  26. 26.
    Boix J, Llecha N, Yuste VJ et al. Characterization of the cell death process induced by staurosporine in human neuroblastome cell lines. Neuropharmacology 1997; 36:811–821.PubMedCrossRefGoogle Scholar
  27. 27.
    Walker PR, Leblanc J, Carson C et al. Neither caspase-3 nor DNA fragmentation factor is required for high molecular weight DNA degradation in Apoptosis. Ann NY Acad Sci 1999; 887:48–59.PubMedCrossRefGoogle Scholar
  28. 28.
    Yuste VJ, Bayascas JR, Llecha N et al. The absence of oligonucleosomal DNA fragmentation during apoptosis of IMR-5, neuroblastoma cells. J Biol Chem 2001; 276:22323–22331.PubMedCrossRefGoogle Scholar
  29. 29.
    Nagata S, Nagasake H, Kawane K et al. Degradation of chromosomal DNA during apoptosis. Cell Death Differ 2003; 10:108–116.PubMedCrossRefGoogle Scholar
  30. 30.
    Negoescu A, Guillermet C, Lorimier P et al. Importance of DNA fragmentation in apoptosis with regard to TUNEL specificity. Biomed & Pharmacother 1998; 52:252–258.CrossRefGoogle Scholar
  31. 31.
    Pulkkanen KJ, Laukkanen MO, Naarala J et al. False-positive apoptosis signal in mouse kidley and liver detected with TUNEL assay. Apoptosis 2000; 5:329–333.PubMedCrossRefGoogle Scholar
  32. 32.
    Mpoke SS, Wolfe J. DNA digestion and chromatin condensation during nuclear death in Tetrahymena. Exp Cell Res 1996; 225:357–365.PubMedCrossRefGoogle Scholar
  33. 33.
    Batistatou A, Greene LA. Intranucleosomal DNA cleavage and neuronal cell survival/death. J Cell Biol 1993; 122:523–532.PubMedCrossRefGoogle Scholar
  34. 34.
    Nanney D. Nucleocytoplasmic interaction during the conjugation in Tetrahymena. Biol Bull 1953; 105:133–148.CrossRefGoogle Scholar
  35. 35.
    Ameisen JC, Idziorek T, Brillant-Mulot O et al. Apoptosis in a unicellular eukaryote (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell death in the control of cell proliferation, differentiation and survival. Cell Death Differ 1995; 2:285–300.PubMedGoogle Scholar
  36. 36.
    Welburn SC, Dale C, Ellis D et al. Apoptosis in procyclic Trypanosoma brucei rhodesiense in vitro. Cell Death Differ 1996; 3:229–236.PubMedGoogle Scholar
  37. 37.
    Arnoult D, Akarid K, Godet A et al. On the evolution of programmed cell death: apoptosisod the unicellular eukaryote Leishmania major involves cysteine proteinase activation, and mitochondrion permeabilization. Cell Death Differ 2002; 9:65–81.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee N, Bertholet S, Debrabant A et al. Programmed cell death in the unicellular parasite Leishmania. Cell Death Differ 2002; 9:53–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Nasirudeen AMA, Tan KS, Sing M. et al. Programmed cell death in a human intestinal parasite, Blastocystis hominis. Parasitology 2001a; 123:235–246.PubMedCrossRefGoogle Scholar
  40. 40.
    Tan KSW, Nasirudeen AMA. Protozoan programmed cell death-insights from Blastocystis deathstyles. Trends Parasitol 2005; 21:547–550.PubMedCrossRefGoogle Scholar
  41. 41.
    Al-Olayan EM, Williams GT, Hurd H. Apoptosis in the malarian protozoan, Plasmodium bergeri: a possible mechanism for limiting intensity of infection in the mosquito. Int J Parasitol 2002; 32:1133–144.PubMedCrossRefGoogle Scholar
  42. 42.
    Deponte M, Becker K. Plasmodium falciparum-do killers commit suicide? Trends Parasitol 2004; 20:165–169.PubMedCrossRefGoogle Scholar
  43. 43.
    Maheshwari R. Nuclear behavior in fungal hyphae. FEMS Microbiol Lett 2005; 249:7–14.PubMedCrossRefGoogle Scholar
  44. 44.
    Marek SM, Wu J, Glass NL et al. Nuclear DNA degradation during heterokaryon incompatibility in Neurospora crassa. Fungal Genet Biol 2003; 40:126–137.PubMedCrossRefGoogle Scholar
  45. 45.
    Nevzglyadova O, Artyomov AV Mikhailova EV et al. Bud selection and apoptosis-like degradation of nuclei in yeast heterokayons: a KAR1 effect. Mol Gen Genomics 2005; 274:419–427.CrossRefGoogle Scholar
  46. 46.
    Buckland-Nicks J, Tompkins G. Paraspermatogenesis in Ceratostoma foliatum (Neogastropoda): Confirmation of programmed nuclear death. J Exp Zool 2005; 303A:723–741.CrossRefGoogle Scholar
  47. 47.
    Susin SA, Daugas E, Ravagnan L et al. Two distinct pathways leading to nuclear apoptosis. J Exp Med 2000; 192:571–579.PubMedCrossRefGoogle Scholar
  48. 48.
    Kivinen K, Kallajoki M, Taimen P. Caspase-3 is required in the apoptotic disintegration of the nuclear matrix. Exp. Cell Res 2005; 311:62–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Op Cell Biol 2003; 15:725–731.PubMedCrossRefGoogle Scholar
  50. 50.
    Boyce M, Degterev A, Yuan J. Caspases: an ancient cellular sword of Damocles. Cell Death Differ 2004; 11:29–37.PubMedCrossRefGoogle Scholar
  51. 51.
    Garrido C, Kroemer G. Life’s smile, death’s grin: vital functions of apoptosis-executing proteins. Curr Op Cell Biol 2004; 16:639–646.PubMedCrossRefGoogle Scholar
  52. 52.
    Uren AG, O’Rourke K, Aravind LA et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphome. Mol Cell 2000; 6:961–967.PubMedGoogle Scholar
  53. 53.
    Ejercito M, Wolfe J. Caspase-like activity is required for programmed nuclear elimination during conjugation in Tetrahymena. J Euk Microbiol 2003; 50:427–429.PubMedCrossRefGoogle Scholar
  54. 54.
    Kobayashi T, Endoh H. Caspase-like activity in programmed nuclear death during conjugation of Tetrahymena thermophila. Cell Death Differ 2003; 10:634–640.PubMedCrossRefGoogle Scholar
  55. 55.
    Nasirudeen AMA, Singh M, Yap EH et al. Blastocystic hominis: evidence for caspase-3-like activity in cells undergoing programmed cell death. Parasitol Res 2001b: 87:559–565.PubMedCrossRefGoogle Scholar
  56. 56.
    Mottram JC, Helms MJ, Coombs GH et al. Clan CD cysteine peptidases of parasitic protozoa. Trends Parasitol 2003; 19:182–187.PubMedCrossRefGoogle Scholar
  57. 57.
    Zangger H, Mottram JC, Fasel N. Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis? Cell Death Differ 2002; 9:1126–1139.PubMedCrossRefGoogle Scholar
  58. 58.
    Kosec G, Alvarez V, Agüero F et al. Metacaspases in Trypanosoma cruzi: Posible candidates for programmed cell death mediators. Mol Biochem Parasitol 2006; 145:18–28.PubMedCrossRefGoogle Scholar
  59. 59.
    Mpoke SS, Wolfe J. Differential staining of apoptotic nuclei in living cells: Application to macronuclear elimination in Tetrahymena. J Histochem Cytochem 1997; 45:675–683.PubMedGoogle Scholar
  60. 60.
    Lu E, Wolfe J. Lysosomal enzymes in the macronucleus of Tetrahymena during its apoptosis-like degradation. Cell Death Differ 2001; 8:289–297.PubMedCrossRefGoogle Scholar
  61. 61.
    Kobayashi T, Endoh H. A possible role of mitochondria in the apoptotic-like programmed nuclear death of Tetrahymena thermophila. FEBS J 2005; 272:5378–5387.PubMedCrossRefGoogle Scholar
  62. 62.
    Endoh H, Kobayashi T. Death harmony played by nucleus and mitochondria. Nuclear apoptosis during conjugation of Tetrahymena. Autophagy 2006; 2:129–131.PubMedGoogle Scholar
  63. 63.
    Nilsson JR. On starvation-induced autophagy in Tetrahymena. Carsberg Res Commun 1984; 49:323–340.CrossRefGoogle Scholar
  64. 64.
    Dunn WA Jr. Studies of the mechanisms of autophagy: Formation of the autophagic vacuole. J Cell Biol 1990; 110:1923–1933.PubMedCrossRefGoogle Scholar
  65. 65.
    Fok AK, Muraoka JH, Allen RD. Acid phosphatase in the digestive vacuoles and lysosomes of Paramecium caudatum: A timed study. J Euk Microbiol 1984; 31:216–220.CrossRefGoogle Scholar
  66. 66.
    Kiy T, Vosskühler C, Rasmussen L et al. The three pools of lysosomal enzymes in Tetrahymena thermophila. Exp Cell Res 1993; 205:286–292.PubMedCrossRefGoogle Scholar
  67. 67.
    Skotarczak B. The formation of primary and secondary lysosomes in Balantidium coli, Ciliata. Folia Histochem Cytobiol 1999; 37:261–265.PubMedGoogle Scholar
  68. 68.
    Rasmussen L, Florin-Christensen M, Florin-Christensen J et al. Differential increase in activity of acid phosphatase induced by phosphate starvation in Tetrahymena. Exp Cell Res 1992; 201:522–525.PubMedCrossRefGoogle Scholar
  69. 69.
    Maddireddi MT, Davis MC, Allis CD. Identification of a novel polypeptide involved in the formation of DNA-containing vesicles during macronuclear development in Tetrahymena. Dev Biol 1994; 165:418–431.CrossRefGoogle Scholar
  70. 70.
    Maddireddi MT, Coyne RS, Smothers JF et al. Pdd1p, a novel chromodomain-containing protein, links heterochromatin assembly and DNA elimination in Tetrahymena. Cell 1996; 87:75–84.CrossRefGoogle Scholar
  71. 71.
    Mikami K, Hiwatashi K. Macronuclear regeneration and cells division in Paramecium caudatum. J Euk Microbiol 1975; 22:536–540.CrossRefGoogle Scholar
  72. 72.
    Mikami K. Internuclear control of DNA synthesis in exconjugants cells of Paramecium caudatum. Chromosoma 1979; 73:131–142.PubMedCrossRefGoogle Scholar
  73. 73.
    Kimura N, Mikami K. Interactions between newly developed macronuclei and maternal macronuclei in sexually immature multinucleate exconjugants of Paramecium caudatum. Differentiation 2003; 71:337–345.PubMedCrossRefGoogle Scholar
  74. 74.
    Kimura N, Mikami K, Endoh H. Delayed degradation of parental macronuclear DNA in programmed nuclear death in Paramecium. Genesis 2004; 40:15–21.PubMedCrossRefGoogle Scholar
  75. 75.
    Martín-González A, Benítez L, Gutiérrez JC. Cortical and nuclear events during cell division and resting cyst formation in Colpoda inflata. J Euk Microbiol 1991; 38:338–344.CrossRefGoogle Scholar
  76. 76.
    Martín-González A, Palacios G, Gutiérrez JC. Macronuclear chromatin changes during encystment in the ciliate Colpoda inflata: Formation of cristal-like structures in the resting cyst chromatin and nucleolar condensation. Eur J Protistol 2001; 37:121–136.CrossRefGoogle Scholar
  77. 77.
    Baba M, Takehisge K, Baba N et al. Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization. J Cell Biol 1994; 124:903–913.PubMedCrossRefGoogle Scholar
  78. 78.
    Christensen ST, Chemnitz J, Straarup EM et al. Staurosporine-induced cell death in Tetrahymena thermophila has mixed characteristics of both apoptotic and autophagic degeneration. Cell Biol Inter 1998; 22:591–598.CrossRefGoogle Scholar
  79. 79.
    Straarup EM, Sshousboe P, Quie H et al. Effects of protein kinase C activators and staurosporine on cell survival, proliferation and protein kinase activity in Tetrahymena thermophila. Microbios 1997; 91:181–190.PubMedGoogle Scholar
  80. 80.
    Levy MR, Elliot AM. Biochemical and ultrastructural changes in Tetrahymena pyriformis during starvation. J Euk Microbiol 1968; 15:208–222.CrossRefGoogle Scholar
  81. 81.
    Martín-González A, Borniquel S, Díaz S et al. Ultrastructural alterations in ciliated protozoa under heavy metal exposure. Cell Biol Inter 2005; 29:119–126.CrossRefGoogle Scholar
  82. 82.
    Kovács P, Hegyesi H, Köhidai L et al. Effect of C2 ceramide on the inositol phospholipid metabolism (uptake of 32P, 3H-serine and 3H-palmitic acid) and apoptosis-related morphological changes in Tetrahymena. Comp Biochem Physiol C 1999; 122:215–224.PubMedGoogle Scholar
  83. 83.
    Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. TIBS 1995; 20:73–77.PubMedGoogle Scholar
  84. 84.
    Klionsky DJ, Emr S. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290:1717–1721.PubMedCrossRefGoogle Scholar
  85. 85.
    Edinger AL Thompson CR. Death by design: apoptosis, necrosis and autophagy. Curr Op Cell Biol 2004; 16:663–669.PubMedCrossRefGoogle Scholar
  86. 86.
    Scarlatti F, Bauvy C, Ventruti A et al. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of Beclin 1. J Biol Chem 2004; 279:18384–18391.PubMedCrossRefGoogle Scholar
  87. 87.
    Kihara A, Kabeya Y, Ohsumi Y et al. Beclin-phosphatidylinositol 3-kinase complex fuctions at the trans-Golgi network. EMBO reports 2001; 21:330–335.CrossRefGoogle Scholar
  88. 88.
    Hannun YA, Obeid LM. Ceramide-centric universe of lipid-mediated cell regulation: stress encounters the lipid kind. J Biol Chem 2002; 277:25847–25850.PubMedCrossRefGoogle Scholar
  89. 89.
    Hetz CA, Torres V, Queso AFG. Beyond apoptosis: non apoptotic cell death in physiology and disease. Biochem Cell Biol 2002; 83:578–579.Google Scholar
  90. 90.
    Petiot A, Ogier-Denis E, Bloommart EF et al. Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000; 275:992–998.PubMedCrossRefGoogle Scholar
  91. 91.
    Yakisich JS, Kapler GM. The effect of phosphoinositide 3-kinase inhibitors on programmed nuclear degradation in Tetrahymena and the fate of surviving nuclei. Cell Death Differ 2004; 11:1146–1149.PubMedCrossRefGoogle Scholar
  92. 92.
    Walker EH, Pacold ME, Perisic O et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine. Mol Cell 2000; 6:906–919.CrossRefGoogle Scholar
  93. 93.
    Blommaart EF, Krause U, Schellens JP et al. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY 294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 1997; 243:240–246.PubMedCrossRefGoogle Scholar
  94. 94.
    Maercker C, Kortwig H, Nikiforov A et al. A nuclear protein involved in apoptotic-like degradation in Stylonychia: Implications for similar mechanisms in differentiating and starved cells. Mol Biol Cell 1999; 10:3003–3014.PubMedGoogle Scholar
  95. 95.
    Sapra GR, Kloetzel JA. Programmed autophagocytosis accompanying conjugation in the ciliate Stylonychia mytilus. Dev Biol 1975; 42:84–94.PubMedCrossRefGoogle Scholar
  96. 96.
    Chose O, Noel C, Gerbod D et al. A form of cell death with some features resembling apoptosis in the amitochondrial unicellular microorganism Trichomonas vaginalis. Exp Cell Res 2002; 276:32–39.PubMedCrossRefGoogle Scholar
  97. 97.
    Chose O, Sarde C-O, Noel C et al. Cell death in protists without mitochondria. Ann NY Acad Sci 2003a; 1010:121–125.PubMedCrossRefGoogle Scholar
  98. 98.
    Chose O, Sarde C-O, Gerbod D et al. Programmed cell death in parasitic protozoans that lack mitochondria. Trends Parasitol 2003b; 19:559–564.PubMedCrossRefGoogle Scholar
  99. 99.
    Segovia M, Haramaty L, Berges JA et al. Cell death in the unicellular chlorophyte Dunaliella tertiolecta. A hypothesis on the evolution of apoptosis in higher plants and metazoans. Plant Physiol 2003; 132:99–105.PubMedCrossRefGoogle Scholar
  100. 100.
    Ameisen JC. On the origin, evolution and nature of programmed cell death: a timeline of four billion years. Cell Death Differ 2002; 9:367–393.PubMedCrossRefGoogle Scholar
  101. 101.
    Abraham MC, Shaham S. Death without caspases, caspases without death. Trends Cell Biol 2004; 14:184–193.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Ana Martín González
    • 1
  • Silvia Díaz
    • 1
  • Andrea Gallego
    • 1
  • Juan C. Gutiérrez
    • 1
  1. 1.Departamento de Microbiología-III, Facultad de BiologíaUniversidad Complutense (UCM)MadridSpain

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