Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 291 (5507): 1279-1284

Copyright © 2001 by the American Association for the Advancement of Science

Apoptotic Molecular Machinery: Vastly Increased Complexity in Vertebrates Revealed by Genome Comparisons

L. Aravind,1 Vishva M. Dixit,2 Eugene V. Koonin1*

A comparison of the proteins encoded in the recently (nearly) completed human genome to those from the fly and nematode genomes reveals a major increase in the complexity of the apoptotic molecular machinery in vertebrates, in terms of both the number of proteins involved and their domain architecture. Several components of the apoptotic system are shared by humans and flies, to the exclusion of nematodes, which seems to support the existence of a coelomate clade in animal evolution. A considerable repertoire of apoptotic protein domains was detected in Actinomycetes and Cyanobacteria, which suggests a major contribution of horizontal gene transfer to the early evolution of apoptosis.

1 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
2 Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
*   To whom correspondence should be addressed. E-mail: koonin{at}

Somatic embryogenesis: life and death processes during apical-basal patterning.
A. Smertenko and P. V. Bozhkov (2014)
J. Exp. Bot.
   Abstract »    Full Text »    PDF »
Evolution of the Animal Apoptosis Network.
C. M. Zmasek and A. Godzik (2013)
Cold Spring Harb Perspect Biol 5, a008649
   Abstract »    Full Text »    PDF »
Nrf2 Protein Up-regulates Antiapoptotic Protein Bcl-2 and Prevents Cellular Apoptosis.
S. K. Niture and A. K. Jaiswal (2012)
J. Biol. Chem. 287, 9873-9886
   Abstract »    Full Text »    PDF »
Inhibitor of Nrf2 (INrf2 or Keap1) Protein Degrades Bcl-xL via Phosphoglycerate Mutase 5 and Controls Cellular Apoptosis.
S. K. Niture and A. K. Jaiswal (2011)
J. Biol. Chem. 286, 44542-44556
   Abstract »    Full Text »    PDF »
KLF6-SV1 Is a Novel Antiapoptotic Protein That Targets the BH3-Only Protein NOXA for Degradation and Whose Inhibition Extends Survival in an Ovarian Cancer Model.
A. DiFeo, F. Huang, J. Sangodkar, E. A. Terzo, D. Leake, G. Narla, and J. A. Martignetti (2009)
Cancer Res. 69, 4733-4741
   Abstract »    Full Text »    PDF »
Hereditary Spastic Paraplegia-Associated Mutations in the NIPA1 Gene and Its Caenorhabditis elegans Homolog Trigger Neural Degeneration In Vitro and In Vivo through a Gain-of-Function Mechanism.
J. Zhao, D. S. Matthies, E. J. Botzolakis, R. L. Macdonald, R. D. Blakely, and P. Hedera (2008)
J. Neurosci. 28, 13938-13951
   Abstract »    Full Text »    PDF »
Evolutionary origins of human apoptosis and genome-stability gene networks.
M. A. A. Castro, R. J. S. Dalmolin, J. C. F. Moreira, J. C. M. Mombach, and R. M. C. de Almeida (2008)
Nucleic Acids Res. 36, 6269-6283
   Abstract »    Full Text »    PDF »
Importance of Lineage-Specific Expansion of Plant Tandem Duplicates in the Adaptive Response to Environmental Stimuli.
K. Hanada, C. Zou, M. D. Lehti-Shiu, K. Shinozaki, and S.-H. Shiu (2008)
Plant Physiology 148, 993-1003
   Abstract »    Full Text »    PDF »
Programmed Genetic Instability: A Tumor-Permissive Mechanism for Maintaining the Evolvability of Higher Species through Methylation-Dependent Mutation of DNA Repair Genes in the Male Germ Line.
Y. Zhao and R. J. Epstein (2008)
Mol. Biol. Evol. 25, 1737-1749
   Abstract »    Full Text »    PDF »
Identification of Novel Mammalian Caspases Reveals an Important Role of Gene Loss in Shaping the Human Caspase Repertoire.
L. Eckhart, C. Ballaun, M. Hermann, J. L. VandeBerg, W. Sipos, A. Uthman, H. Fischer, and E. Tschachler (2008)
Mol. Biol. Evol. 25, 831-841
   Abstract »    Full Text »    PDF »
Acute lung injury and cell death: how many ways can cells die?.
P. S. Tang, M. Mura, R. Seth, and M. Liu (2008)
Am J Physiol Lung Cell Mol Physiol 294, L632-L641
   Abstract »    Full Text »    PDF »
Evolution of protein domain promiscuity in eukaryotes.
M. K. Basu, L. Carmel, I. B. Rogozin, and E. V. Koonin (2008)
Genome Res. 18, 449-461
   Abstract »    Full Text »    PDF »
Features of Apoptosis in Plasmodium falciparum Erythrocytic Stage through a Putative Role of PfMCA1 Metacaspase-Like Protein.
B. Meslin, C. Barnadas, V. Boni, C. Latour, F. De Monbrison, K. Kaiser, and S. Picot (2007)
The Journal of Infectious Disease 195, 1852-1859
   Abstract »    Full Text »    PDF »
Human Bcl-2 cannot directly inhibit the Caenorhabditis elegans Apaf-1 homologue CED-4, but can interact with EGL-1.
A. M. Jabbour, M. A. Puryer, J. Y. Yu, T. Lithgow, C. D. Riffkin, D. M. Ashley, D. L. Vaux, P. G. Ekert, and C. J. Hawkins (2006)
J. Cell Sci. 119, 2572-2582
   Abstract »    Full Text »    PDF »
The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
C. J. Gloeckner, N. Kinkl, A. Schumacher, R. J. Braun, E. O'Neill, T. Meitinger, W. Kolch, H. Prokisch, and M. Ueffing (2006)
Hum. Mol. Genet. 15, 223-232
   Abstract »    Full Text »    PDF »
Inhibition of MAPK and NF-{kappa}B Pathways Is Necessary for Rapid Apoptosis in Macrophages Infected with Yersinia.
Y. Zhang, A. T. Ting, K. B. Marcu, and J. B. Bliska (2005)
J. Immunol. 174, 7939-7949
   Abstract »    Full Text »    PDF »
Apoptosis Induced by the Toll-Like Receptor Adaptor TRIF Is Dependent on Its Receptor Interacting Protein Homotypic Interaction Motif.
W. J. Kaiser and M. K. Offermann (2005)
J. Immunol. 174, 4942-4952
   Abstract »    Full Text »    PDF »
Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani.
N. K. Verma and C. S. Dey (2004)
Antimicrob. Agents Chemother. 48, 3010-3015
   Abstract »    Full Text »    PDF »
Leishmania major-mediated prevention of programmed cell death induction in infected macrophages is associated with the repression of mitochondrial release of cytochrome c.
K. Akarid, D. Arnoult, J. Micic-Polianski, J. Sif, J. Estaquier, and J. C. Ameisen (2004)
J. Leukoc. Biol. 76, 95-103
   Abstract »    Full Text »    PDF »
SOCS-1 suppresses TNF-{alpha}-induced apoptosis through the regulation of Jak activation.
A. Kimura, T. Naka, S. Nagata, I. Kawase, and T. Kishimoto (2004)
Int. Immunol. 16, 991-999
   Abstract »    Full Text »    PDF »
Requirement of IFI16 for the Maximal Activation of p53 Induced by Ionizing Radiation.
N. Fujiuchi, J. A. Aglipay, T. Ohtsuka, N. Maehara, F. Sahin, G. H. Su, S. W. Lee, and T. Ouchi (2004)
J. Biol. Chem. 279, 20339-20344
   Abstract »    Full Text »    PDF »
Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes.
C. Paris, P. M. Loiseau, C. Bories, and J. Breard (2004)
Antimicrob. Agents Chemother. 48, 852-859
   Abstract »    Full Text »    PDF »
Coupling of caspase-9 to Apaf1 in response to loss of pRb or cytotoxic drugs is cell-type-specific.
A. T. Ho, Q. H. Li, R. Hakem, T. W. Mak, and E. Zacksenhaus (2004)
EMBO J. 23, 460-472
   Abstract »    Full Text »    PDF »
Caspases function in autophagic programmed cell death in Drosophila.
D. N. Martin and E. H. Baehrecke (2004)
Development 131, 275-284
   Abstract »    Full Text »    PDF »
A Bax/Bak-independent Mitochondrial Death Pathway Triggered by Drosophila Grim GH3 Domain in Mammalian Cells.
C. Claveria, C. Martinez-A, and M. Torres (2004)
J. Biol. Chem. 279, 1368-1375
   Abstract »    Full Text »    PDF »
Neurogenetics: single gene disorders.
S-M Pulst (2003)
J. Neurol. Neurosurg. Psychiatry 74, 1608-1614
   Abstract »    Full Text »    PDF »
Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog.
Y. Zhang, M. I. Dawson, Y. Ning, L. Polin, R. E. Parchment, T. Corbett, A. N. Mohamed, K.-C. Feng, L. Farhana, A. K. Rishi, et al. (2003)
Blood 102, 3743-3752
   Abstract »    Full Text »    PDF »
Induction of PYPAF1 during In Vitro Maturation of Mouse Mast Cells.
R. Kikuchi-Yanoshita, Y. Taketomi, K. Koga, T. Sugiki, Y. Atsumi, T. Saito, S.-i. Ishii, M. Hisada, T. Suzuki-Nishimura, M. K. Uchida, et al. (2003)
J. Biochem. 134, 699-709
   Abstract »    Full Text »    PDF »
CARD6 Is a Modulator of NF-{kappa}B Activation by Nod1- and Cardiak-mediated Pathways.
C. Stehlik, H. Hayashi, F. Pio, A. Godzik, and J. C. Reed (2003)
J. Biol. Chem. 278, 31941-31949
   Abstract »    Full Text »    PDF »
Buffy, a Drosophila Bcl-2 protein, has anti-apoptotic and cell cycle inhibitory functions.
L. Quinn, M. Coombe, K. Mills, T. Daish, P. Colussi, S. Kumar, and H. Richardson (2003)
EMBO J. 22, 3568-3579
   Abstract »    Full Text »    PDF »
The Protein Tyrosine Phosphatase SHP-2 Regulates Interleukin-1-induced ERK Activation in Fibroblasts.
M. MacGillivray, M. T. Herrera-Abreu, C.-W. Chow, C. Shek, Q. Wang, E. Vachon, G.-S. Feng, K. A. Siminovitch, C. A. G. McCulloch, and G. P. Downey (2003)
J. Biol. Chem. 278, 27190-27198
   Abstract »    Full Text »    PDF »
Cell Death in the Unicellular Chlorophyte Dunaliella tertiolecta. A Hypothesis on the Evolution of Apoptosis in Higher Plants and Metazoans.
M. Segovia, L. Haramaty, J. A. Berges, and P. G. Falkowski (2003)
Plant Physiology 132, 99-105
   Abstract »    Full Text »    PDF »
Caspy, a Zebrafish Caspase, Activated by ASC Oligomerization Is Required for Pharyngeal Arch Development.
J. Masumoto, W. Zhou, F. F. Chen, F. Su, J. Y. Kuwada, E. Hidaka, T. Katsuyama, J. Sagara, S.'i. Taniguchi, P. Ngo-Hazelett, et al. (2003)
J. Biol. Chem. 278, 4268-4276
   Abstract »    Full Text »    PDF »
Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?.
C. Cande, F. Cecconi, P. Dessen, and G. Kroemer (2002)
J. Cell Sci. 115, 4727-4734
   Abstract »    Full Text »    PDF »
Death-associated Protein 4 Binds MST1 and Augments MST1-induced Apoptosis.
Y. Lin, A. Khokhlatchev, D. Figeys, and J. Avruch (2002)
J. Biol. Chem. 277, 47991-48001
   Abstract »    Full Text »    PDF »
The Role of Lineage-Specific Gene Family Expansion in the Evolution of Eukaryotes.
O. Lespinet, Y. I. Wolf, E. V. Koonin, and L. Aravind (2002)
Genome Res. 12, 1048-1059
   Abstract »    Full Text »    PDF »
Programmed cell death takes flight: genetic and genomic approaches to gene discovery in Drosophila.
S. Gorski and M. Marra (2002)
Physiol Genomics 9, 59-69
   Abstract »    Full Text »    PDF »
IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase.
S. Li, A. Strelow, E. J. Fontana, and H. Wesche (2002)
PNAS 99, 5567-5572
   Abstract »    Full Text »    PDF »
Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice.
C. H. Regnier, R. Masson, V. Kedinger, J. Textoris, I. Stoll, M.-P. Chenard, A. Dierich, C. Tomasetto, and M.-C. Rio (2002)
PNAS 99, 5585-5590
   Abstract »    Full Text »    PDF »
Comparative genomics and evolution of proteins involved in RNA metabolism.
V. Anantharaman, E. V. Koonin, and L. Aravind (2002)
Nucleic Acids Res. 30, 1427-1464
   Abstract »    Full Text »    PDF »
A pathway of signals regulating effector and initiator caspases in the developing Drosophila eye.
S.-Y. Yu, S. J. Yoo, L. Yang, C. Zapata, A. Srinivasan, B. A. Hay, and N. E. Baker (2002)
Development 129, 3269-3278
   Abstract »    Full Text »    PDF »
The expanding role of mitochondria in apoptosis.
X. Wang (2001)
Genes & Dev. 15, 2922-2933
   Full Text »    PDF »
High efficiency gene transfer is an efficient way of defining therapeutic targets: a functional genomics approach.
B M J Foxwell, S Yoshimura, J Bondeson, F M Brennan, and M Feldmann (2001)
Ann Rheum Dis 60, iii13-17
   Abstract »    Full Text »    PDF »
Interaction between Pyrin and the Apoptotic Speck Protein (ASC) Modulates ASC-induced Apoptosis.
N. Richards, P. Schaner, A. Diaz, J. Stuckey, E. Shelden, A. Wadhwa, and D. L. Gumucio (2001)
J. Biol. Chem. 276, 39320-39329
   Abstract »    Full Text »    PDF »
NF-{kappa}B signaling pathways in mammalian and insect innate immunity.
N. Silverman and T. Maniatis (2001)
Genes & Dev. 15, 2321-2342
   Full Text »    PDF »
Scale-Free Behavior in Protein Domain Networks.
S. Wuchty (2001)
Mol. Biol. Evol. 18, 1694-1702
   Abstract »    Full Text »    PDF »
Functional antagonism between E2F family members.
M. V. Frolov, D. S. Huen, O. Stevaux, D. Dimova, K. Balczarek-Strang, M. Elsdon, and N. J. Dyson (2001)
Genes & Dev. 15, 2146-2160
   Abstract »    Full Text »    PDF »
FADD-deficient T Cells Exhibit a Disaccord in Regulation of the Cell Cycle Machinery.
J. Zhang, N. H. Kabra, D. Cado, C. Kang, and A. Winoto (2001)
J. Biol. Chem. 276, 29815-29818
   Abstract »    Full Text »    PDF »
Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice.
C. H. Regnier, R. Masson, V. Kedinger, J. Textoris, I. Stoll, M.-P. Chenard, A. Dierich, C. Tomasetto, and M.-C. Rio (2002)
PNAS 99, 5585-5590
   Abstract »    Full Text »    PDF »
Evolutionary perspective on innate immune recognition.
A. Mushegian and R. Medzhitov (2001)
J. Cell Biol. 155, 705-710
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882