Razqallah Hakem1,2, Anne Hakem1,2, Gordon S. Duncan1,2, Jeffrey T. Henderson3, Minna Woo1,2, Maria S. Soengas4, Andrew Elia1,2, José Luis de la Pompa1,2, David Kagi1,2, Wilson Khoo1,2, Julia Potter1,2, Ritsuko Yoshida1,2, Stephen A. Kaufman5, Scott W. Lowe4, Josef M. Penninger1,2 and Tak W. Mak1,2
1 Amgen Institute and
2 Ontario Cancer Institute andDepartments of Medical Biophysics and Immunology, University of TorontoToronto, Ontario, Canada M5G 2C1
3 Samuel Lunenfeld Research Institute, Mount SinaiHospital,
Program in Molecular Biology and CancerHealth, 600 University Ave., Toronto, Ontario M5G-1X5
4 4Cold Spring Harbor Laboratory, Cold Spring Harbor, New York,11724 USA
5 Amgen Institute, Thousand Oaks, CA 91320-1789 USA
Cell, 94, pp. 339-352, 1998
Abstract
Mutation of caspase 9 results in embryonic lethality and defective brain development associated with decreased apoptosis. Caspase 9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV- and g-irradiation. Caspase 9-/- thymocytes are also resistant to dexamethasone- and g-irradiation-induced apoptosis, but surprisingly sensitive to apoptosis induced by UV-irradiation or anti-CD95. Resistance to apoptosis is accompanied by retention of the mitochondrial membrane potential in mutant cells. In addition, cytochrome c is translocated to the cytosol of caspase 9-/- ES cells upon UV-stimulation, suggesting that caspase 9 acts downstream of cytochrome c. Caspase processing is inhibited in caspase 9-/- ES cells but not in thymocytes or splenocytes. Comparison of the requirement for caspase 9 and caspase 3 in different apoptotic settings indicates the existence of at least four different apoptotic pathways in mammalian cells.
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