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Apaf-1 and Caspase-9 Accelerate Apoptosis, but Do Not Determine Whether Factor-Deprived or Drug-Treated Cells Die

Paul G. Ekert, Stuart H. Read, John Silke, Vanessa S. Marsden, Hitto Kaufmann, Christine J. Hawkins, Robert Gerl, Sharad Kumar and David L. Vaux
The Journal of Cell Biology
Vol. 165, No. 6 (Jun. 21, 2004), pp. 835-842
Stable URL: http://www.jstor.org/stable/1622172
Page Count: 8
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Apaf-1 and Caspase-9 Accelerate Apoptosis, but Do Not Determine Whether Factor-Deprived or Drug-Treated Cells Die
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Abstract

Apoptosis after growth factor withdrawal or drug treatment is associated with mitochondrial cytochrome c release and activation of Apaf-1 and caspase-9. To determine whether loss of Apaf-1, caspase-2, and caspase-9 prevented death of factor-starved cells, allowing them to proliferate when growth factor was returned, we generated IL-3-dependent myeloid lines from gene-deleted mice. Long after growth factor removal, cells lacking Apaf-1, caspase-9 or both caspase-9 and caspase-2 appeared healthy, retained intact plasma membranes, and did not expose phosphatidylserine. However, release of cytochrome c still occurred, and they failed to form clones when IL-3 was restored. Cells lacking caspase-2 alone had no survival advantage. Therefore, Apaf-1, caspase-2, and caspase-9 are not required for programmed cell death of factor-dependent cells, but merely affect its rate. In contrast, transfection with Bcl-2 provided long-term, clonogenic protection, and could act independently of the apoptosome. Unlike expression of Bcl-2, loss of Apaf-1, caspase-2, or caspase-9 would therefore be unlikely to enhance the survival of cancer cells.

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