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Science 311 (5762): 847-851

Copyright © 2006 by the American Association for the Advancement of Science

Caspases 3 and 7: Key Mediators of Mitochondrial Events of Apoptosis

Saquib A. Lakhani,1,2 Ali Masud,1,2 Keisuke Kuida,6 George A. Porter, Jr.,2 Carmen J. Booth,3 Wajahat Z. Mehal,1,4 Irteza Inayat,4 Richard A. Flavell1,5*

Abstract: The current model of apoptosis holds that upstream signals lead to activation of downstream effector caspases. We generated mice deficient in the two effectors, caspase 3 and caspase 7, which died immediately after birth with defects in cardiac development. Fibroblasts lacking both enzymes were highly resistant to both mitochondrial and death receptor–mediated apoptosis, displayed preservation of mitochondrial membrane potential, and had defective nuclear translocation of apoptosis-inducing factor (AIF). Furthermore, the early apoptotic events of Bax translocation and cytochrome c release were also delayed. We conclude that caspases 3 and 7 are critical mediators of mitochondrial events of apoptosis.

1 Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2 Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
3 Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
5 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
6 Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, MA 02139, USA.

* To whom correspondence should be addressed. E-mail: richard.flavell{at}yale.edu

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Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity: role of inducible nitric oxide synthase.
J. G. Kiang, P. D. Bowman, X. Lu, Y. Li, B. W. Wu, H. H. Loh, K. T. Tsen, and G. C. Tsokos (2007)
J Appl Physiol 103, 1045-1055
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XIAP Activity Dictates Apaf-1 Dependency for Caspase 9 Activation.
A. T. Ho, Q. H. Li, H. Okada, T. W. Mak, and E. Zacksenhaus (2007)
Mol. Cell. Biol. 27, 5673-5685
   Abstract »    Full Text »    PDF »
Caspase 7 influences susceptibility to rheumatoid arthritis.
J. R. Garcia-Lozano, B. Torres, O. Fernandez, G. Orozco, A. Alvarez-Marquez, A. Garcia, M. A. Gonzalez-Gay, A. Garcia, A. Nunez-Roldan, J. Martin, et al. (2007)
Rheumatology 46, 1243-1247
   Abstract »    Full Text »    PDF »
An L-Tyrosine Derivative and PPAR{gamma} Agonist, GW7845, Activates a Multifaceted Caspase Cascade in Bone Marrow B Cells.
J. J. Schlezinger, J. K. Emberley, S. L. Bissonnette, and D. H. Sherr (2007)
Toxicol. Sci. 98, 125-136
   Abstract »    Full Text »    PDF »
Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death.
C. W. Yde, M. Gyrd-Hansen, A. E. Lykkesfeldt, O.-G. Issinger, and J. Stenvang (2007)
Mol. Cancer Ther. 6, 1869-1876
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress-induced Death of Mouse Embryonic Fibroblasts Requires the Intrinsic Pathway of Apoptosis.
A. Masud, A. Mohapatra, S. A. Lakhani, A. Ferrandino, R. Hakem, and R. A. Flavell (2007)
J. Biol. Chem. 282, 14132-14139
   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 »
Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization.
R. Blomgran, L. Zheng, and O. Stendahl (2007)
J. Leukoc. Biol. 81, 1213-1223
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Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma.
A. H. Stegh, H. Kim, R. M. Bachoo, K. L. Forloney, J. Zhang, H. Schulze, K. Park, G. J. Hannon, J. Yuan, D. N. Louis, et al. (2007)
Genes & Dev. 21, 98-111
   Abstract »    Full Text »    PDF »
Is caspase-dependent apoptosis only cell differentiation taken to the extreme?.
P. Fernando and L. A. Megeney (2007)
FASEB J 21, 8-17
   Abstract »    Full Text »    PDF »
Mitoenergetic failure in Alzheimer disease.
M. S Parihar and G. J. Brewer (2007)
Am J Physiol Cell Physiol 292, C8-C23
   Abstract »    Full Text »    PDF »
p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase-Mediated Caspase-9 Activation.
D. Sohn, F. Essmann, K. Schulze-Osthoff, and R. U. Janicke (2006)
Cancer Res. 66, 11254-11262
   Abstract »    Full Text »    PDF »
Sitosterol-containing Lipoproteins Trigger Free Sterol-induced Caspase-independent Death in ACAT-competent Macrophages.
L. Bao, Y. Li, S.-X. Deng, D. Landry, and I. Tabas (2006)
J. Biol. Chem. 281, 33635-33649
   Abstract »    Full Text »    PDF »

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