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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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Essential Role for Signal Transducer and Activator of Transcription-1 in Pancreatic {beta}-Cell Death and Autoimmune Type 1 Diabetes of Nonobese Diabetic Mice.
S. Kim, H. S. Kim, K. W. Chung, S. H. Oh, J. W. Yun, S.-H. Im, M.-K. Lee, K.-W. Kim, and M.-S. Lee (2007)
Diabetes 56, 2561-2568
   Abstract »    Full Text »    PDF »
Neutral sphingomyelinase-induced ceramide triggers germinal vesicle breakdown and oxidant-dependent apoptosis in Xenopus laevis oocytes.
O. Coll, A. Morales, J. C. Fernandez-Checa, and C. Garcia-Ruiz (2007)
J. Lipid Res. 48, 1924-1935
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis.
A. I. Nieminen, J. I. Partanen, A. Hau, and J. Klefstrom (2007)
EMBO J. 26, 1055-1067
   Abstract »    Full Text »    PDF »
Bak and Bax are non-redundant during infection- and DNA damage-induced apoptosis.
O. Kepp, K. Rajalingam, S. Kimmig, and T. Rudel (2007)
EMBO J. 26, 825-834
   Abstract »    Full Text »    PDF »

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