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.

Originally published in Science Express on 8 April 2004
Science 7 May 2004:
Vol. 304. no. 5672, pp. 843 - 846
DOI: 10.1126/science.1095432
Prev | Table of Contents | Next

Research Articles

The PIDDosome, a Protein Complex Implicated in Activation of Caspase-2 in Response to Genotoxic Stress

Antoine Tinel and Jürg Tschopp*

Apoptosis is triggered by activation of initiator caspases upon complex-mediated clustering of the inactive zymogen, as occurs in the caspase-9–activating apoptosome complex. Likewise, caspase-2, which is involved in stress-induced apoptosis, is recruited into a large protein complex, the molecular composition of which remains elusive. We show that activation of caspase-2 occurs in a complex that contains the death domain–containing protein PIDD, whose expression is induced by p53, and the adaptor protein RAIDD. Increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli. Because PIDD functions in p53-mediated apoptosis, the complex assembled by PIDD and caspase-2 is likely to regulate apoptosis induced by genotoxins.

Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.

* To whom correspondence should be addressed. E-mail: jurg.tschopp{at}ib.unil.ch

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Hepatitis C Virus Core Protein and Cellular Protein HAX-1 Promote 5-Fluorouracil-Mediated Hepatocyte Growth Inhibition.
A. Banerjee, K. Saito, K. Meyer, S. Banerjee, M. Ait-Goughoulte, R. B. Ray, and R. Ray (2009)
J. Virol. 83, 9663-9671
   Abstract »    Full Text »    PDF »
Etoposide Induces Protein Kinase C{delta}- and Caspase-3-Dependent Apoptosis in Neuroblastoma Cancer Cells.
T. W. Day, C.-H. Wu, and A. R. Safa (2009)
Mol. Pharmacol. 76, 632-640
   Abstract »    Full Text »    PDF »
Apoptosis and cancer: mutations within caspase genes.
S Ghavami, M Hashemi, S R Ande, B Yeganeh, W Xiao, M Eshraghi, C J Bus, K Kadkhoda, E Wiechec, A J Halayko, et al. (2009)
J. Med. Genet. 46, 497-510
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase-3{beta} Mediates Endoplasmic Reticulum Stress-Induced Lysosomal Apoptosis in Leukemia.
W.-C. Huang, Y.-S. Lin, C.-L. Chen, C.-Y. Wang, W.-H. Chiu, and C.-F. Lin (2009)
J. Pharmacol. Exp. Ther. 329, 524-531
   Abstract »    Full Text »    PDF »
Caspase-2 activation in the absence of PIDDosome formation.
C. Manzl, G. Krumschnabel, F. Bock, B. Sohm, V. Labi, F. Baumgartner, E. Logette, J. Tschopp, and A. Villunger (2009)
J. Cell Biol. 185, 291-303
   Abstract »    Full Text »    PDF »
Cordycepin Induced MA-10 Mouse Leydig Tumor Cell Apoptosis through Caspase-9 Pathway.
C.-Y. Jen, C.-Y. Lin, S.-F. Leu, and B.-M. Huang (2009)
Evid. Based Complement. Altern. Med.
   Abstract »    Full Text »    PDF »
Signalling loops and linear pathways: NF-{kappa}B activation in response to genotoxic stress.
K. Brzoska and I. Szumiel (2009)
Mutagenesis 24, 1-8
   Abstract »    Full Text »    PDF »
Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.
F. Gonzalvez, Z. T. Schug, R. H. Houtkooper, E. D. MacKenzie, D. G. Brooks, R. J.A. Wanders, P. X. Petit, F. M. Vaz, and E. Gottlieb (2008)
J. Cell Biol. 183, 681-696
   Abstract »    Full Text »    PDF »
Regulation and Pathological Role of p53 in Cisplatin Nephrotoxicity.
M. Jiang and Z. Dong (2008)
J. Pharmacol. Exp. Ther. 327, 300-307
   Abstract »    Full Text »    PDF »
The PIDDosome mediates delayed death of hippocampal CA1 neurons after transient global cerebral ischemia in rats.
K. Niizuma, H. Endo, C. Nito, D. J. Myer, G. S. Kim, and P. H. Chan (2008)
PNAS 105, 16368-16373
   Abstract »    Full Text »    PDF »
Cytolethal Distending Toxin Induces Caspase-Dependent and -Independent Cell Death in MOLT-4 Cells.
M. Ohara, T. Hayashi, Y. Kusunoki, K. Nakachi, T. Fujiwara, H. Komatsuzawa, and M. Sugai (2008)
Infect. Immun. 76, 4783-4791
   Abstract »    Full Text »    PDF »
Caspase-2: Vestigial Remnant or Master Regulator?.
C. M. Troy and E. M. Ribe (2008)
Science Signaling 1, pe42
   Abstract »    Full Text »    PDF »
Proapoptotic Activity and Chemosensitizing Effect of the Novel Akt Inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-Cell Acute Lymphoblastic Leukemia.
F. Fala, W. L. Blalock, P. L. Tazzari, A. Cappellini, F. Chiarini, G. Martinelli, A. Tafuri, J. A. McCubrey, L. Cocco, and A. M. Martelli (2008)
Mol. Pharmacol. 74, 884-895
   Abstract »    Full Text »    PDF »
Caspase-2 Cleavage of BID Is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress.
J.-P. Upton, K. Austgen, M. Nishino, K. M. Coakley, A. Hagen, D. Han, F. R. Papa, and S. A. Oakes (2008)
Mol. Cell. Biol. 28, 3943-3951
   Abstract »    Full Text »    PDF »
Down-regulation of Caspase-2 by Rottlerin via Protein Kinase C-{delta}-Independent Pathway.
A. Basu, B. Adkins, and C. Basu (2008)
Cancer Res. 68, 2795-2802
   Abstract »    Full Text »    PDF »
A role for caspase 2 and PIDD in the process of p53-mediated apoptosis.
N. Baptiste-Okoh, A. M. Barsotti, and C. Prives (2008)
PNAS 105, 1937-1942
   Abstract »    Full Text »    PDF »
BCL-2 Family Proteins: Critical Checkpoints of Apoptotic Cell Death.
N. N. Danial (2007)
Clin. Cancer Res. 13, 7254-7263
   Abstract »    Full Text »    PDF »
Caspase-9-induced Mitochondrial Disruption through Cleavage of Anti-apoptotic BCL-2 Family Members.
M. Chen, A. D. Guerrero, L. Huang, Z. Shabier, M. Pan, T.-H. Tan, and J. Wang (2007)
J. Biol. Chem. 282, 33888-33895
   Abstract »    Full Text »    PDF »
GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis.
C.-F. Lin, C.-L. Chen, C.-W. Chiang, M.-S. Jan, W.-C. Huang, and Y.-S. Lin (2007)
J. Cell Sci. 120, 2935-2943
   Abstract »    Full Text »    PDF »
Interaction of a Cyclin E Fragment with Ku70 Regulates Bax-Mediated Apoptosis.
S. Mazumder, D. Plesca, M. Kinter, and A. Almasan (2007)
Mol. Cell. Biol. 27, 3511-3520
   Abstract »    Full Text »    PDF »
Docetaxel-induced apoptosis in melanoma cells is dependent on activation of caspase-2.
N. M. Mhaidat, Y. Wang, K. A. Kiejda, X. D. Zhang, and P. Hersey (2007)
Mol. Cancer Ther. 6, 752-761
   Abstract »    Full Text »    PDF »
Deregulation of apoptosis in acute myeloid leukemia.
U. Testa and R. Riccioni (2007)
Haematologica 92, 81-94
   Abstract »    Full Text »    PDF »
Loss of Caspase-9 Reveals Its Essential Role for Caspase-2 Activation and Mitochondrial Membrane Depolarization.
A. K. Samraj, D. Sohn, K. Schulze-Osthoff, and I. Schmitz (2007)
Mol. Biol. Cell 18, 84-93
   Abstract »    Full Text »    PDF »
Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer.
B. Oskouian, P. Sooriyakumaran, A. D. Borowsky, A. Crans, L. Dillard-Telm, Y. Y. Tam, P. Bandhuvula, and J. D. Saba (2006)
PNAS 103, 17384-17389
   Abstract »    Full Text »    PDF »
Regulation and Function of IKK and IKK-Related Kinases.
H. Hacker and M. Karin (2006)
Sci. STKE 2006, re13
   Abstract »    Full Text »    PDF »
Osmotic Stress Activates the TAK1-JNK Pathway While Blocking TAK1-mediated NF-{kappa}B Activation: TAO2 REGULATES TAK1 PATHWAYS.
W.-C. HuangFu, E. Omori, S. Akira, K. Matsumoto, and J. Ninomiya-Tsuji (2006)
J. Biol. Chem. 281, 28802-28810
   Abstract »    Full Text »    PDF »
Caspase-2 is activated at the CD95 death-inducing signaling complex in the course of CD95-induced apoptosis.
I. N. Lavrik, A. Golks, S. Baumann, and P. H. Krammer (2006)
Blood 108, 559-565
   Abstract »    Full Text »    PDF »
Caspase-2 Triggers Bax-Bak-dependent and -independent Cell Death in Colon Cancer Cells Treated with Resveratrol.
J. Mohan, A. A. Gandhi, B. C. Bhavya, R. Rashmi, D. Karunagaran, R. Indu, and T. R. Santhoshkumar (2006)
J. Biol. Chem. 281, 17599-17611
   Abstract »    Full Text »    PDF »
Heat Shock Induces Apoptosis Independently of Any Known Initiator Caspase-activating Complex.
R. S. Milleron and S. B. Bratton (2006)
J. Biol. Chem. 281, 16991-17000
   Abstract »    Full Text »    PDF »
The NS5A Protein of the Hepatitis C Virus Genotype 1a Is Cleaved by Caspases to Produce C-terminal-truncated Forms of the Protein That Reside Mainly in the Cytosol.
M. Kalamvoki, U. Georgopoulou, and P. Mavromara (2006)
J. Biol. Chem. 281, 13449-13462
   Abstract »    Full Text »    PDF »
Caspase-2-induced Apoptosis Requires Bid Cleavage: A Physiological Role for Bid in Heat Shock-induced Death.
C. Bonzon, L. Bouchier-Hayes, L. J. Pagliari, D. R. Green, and D. D. Newmeyer (2006)
Mol. Biol. Cell 17, 2150-2157
   Abstract »    Full Text »    PDF »
Caspases leave the beaten track: caspase-mediated activation of NF-{kappa}B.
M. Lamkanfi, W. Declercq, T. Vanden Berghe, and P. Vandenabeele (2006)
J. Cell Biol. 173, 165-171
   Abstract »    Full Text »    PDF »
Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL.
J. S. Carew, S. T. Nawrocki, Y. V. Krupnik, K. Dunner Jr, D. J. McConkey, M. J. Keating, and P. Huang (2006)
Blood 107, 222-231
   Abstract »    Full Text »    PDF »
Essential Roles of the Bcl-2 Family of Proteins in Caspase-2-induced Apoptosis.
Z. Gao, Y. Shao, and X. Jiang (2005)
J. Biol. Chem. 280, 38271-38275
   Abstract »    Full Text »    PDF »
Caspase-2, a Novel Lipid Sensor under the Control of Sterol Regulatory Element Binding Protein 2.
E. Logette, C. Le Jossic-Corcos, D. Masson, S. Solier, A. Sequeira-Legrand, I. Dugail, S. Lemaire-Ewing, L. Desoche, E. Solary, and L. Corcos (2005)
Mol. Cell. Biol. 25, 9621-9631
   Abstract »    Full Text »    PDF »
Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD.
C. Berube, L.-M. Boucher, W. Ma, A. Wakeham, L. Salmena, R. Hakem, W.-C. Yeh, T. W. Mak, and S. Benchimol (2005)
PNAS 102, 14314-14320
   Abstract »    Full Text »    PDF »
Id3 Induces Growth Arrest and Caspase-2-Dependent Apoptosis in B Lymphocyte Progenitors.
B. L. Kee (2005)
J. Immunol. 175, 4518-4527
   Abstract »    Full Text »    PDF »
WMC-79, a potent agent against colon cancers, induces apoptosis through a p53-dependent pathway.
T. Kosakowska-Cholody, W. M. Cholody, A. Monks, B. A. Woynarowska, and C. J. Michejda (2005)
Mol. Cancer Ther. 4, 1617-1627
   Abstract »    Full Text »    PDF »
p53-dependent Caspase-2 Activation in Mitochondrial Release of Apoptosis-inducing Factor and Its Role in Renal Tubular Epithelial Cell Injury.
R. Seth, C. Yang, V. Kaushal, S. V. Shah, and G. P. Kaushal (2005)
J. Biol. Chem. 280, 31230-31239
   Abstract »    Full Text »    PDF »
Bcl-2 Rescues Ceramide- and Etoposide-induced Mitochondrial Apoptosis through Blockage of Caspase-2 Activation.
C.-F. Lin, C.-L. Chen, W.-T. Chang, M.-S. Jan, L.-J. Hsu, R.-H. Wu, Y.-T. Fang, M.-J. Tang, W.-C. Chang, and Y.-S. Lin (2005)
J. Biol. Chem. 280, 23758-23765
   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 »
A Novel Caspase-2 Complex Containing TRAF2 and RIP1.
M. Lamkanfi, K. D'hondt, L. Vande Walle, M. van Gurp, G. Denecker, J. Demeulemeester, M. Kalai, W. Declercq, X. Saelens, and P. Vandenabeele (2005)
J. Biol. Chem. 280, 6923-6932
   Abstract »    Full Text »    PDF »
Newcomers in the process of mitochondrial permeabilization.
S. Lucken-Ardjomande and J.-C. Martinou (2005)
J. Cell Sci. 118, 473-483
   Abstract »    Full Text »    PDF »
The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development.
J. Ren, M. Shi, R. Liu, Q.-H. Yang, T. Johnson, W. C. Skarnes, and C. Du (2005)
PNAS 102, 565-570
   Abstract »    Full Text »    PDF »
Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death.
S. Bergeron, M. Beauchemin, and R. Bertrand (2004)
Mol. Cancer Ther. 3, 1659-1669
   Abstract »    Full Text »    PDF »
Caspase-2 Permeabilizes the Outer Mitochondrial Membrane and Disrupts the Binding of Cytochrome c to Anionic Phospholipids.
M. Enoksson, J. D. Robertson, V. Gogvadze, P. Bu, A. Kropotov, B. Zhivotovsky, and S. Orrenius (2004)
J. Biol. Chem. 279, 49575-49578
   Abstract »    Full Text »    PDF »
Migrate, Differentiate, Proliferate, or Die: Pleiotropic Functions of an Apical "Apoptotic Caspase".
S. Kumar (2004)
Sci. STKE 2004, pe49
   Abstract »    Full Text »    PDF »
Sequential Caspase-2 and Caspase-8 Activation Upstream of Mitochondria during Ceramideand Etoposide-induced Apoptosis.
C.-F. Lin, C.-L. Chen, W.-T. Chang, M.-S. Jan, L.-J. Hsu, R.-H. Wu, M.-J. Tang, W.-C. Chang, and Y.-S. Lin (2004)
J. Biol. Chem. 279, 40755-40761
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)