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Published 21 June 2004. doi:10.1083/jcb.200312031
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 6, 835-842
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Article

Apaf-1 and caspase-9 accelerate apoptosis, but do not determine whether factor-deprived or drug-treated cells die



Paul G. Ekert1,2,3, Stuart H. Read4, John Silke1, Vanessa S. Marsden1, Hitto Kaufmann1, Christine J. Hawkins2, Robert Gerl1, Sharad Kumar4, and David L. Vaux1

1 The Walter and Eliza Hall Institute for Medical Research, Victoria 3050, Australia
2 Murdoch Children's Research Institute, Victoria 3052, Australia
3 Department of Neonatology Royal Children's Hospital, Victoria 3052, Australia
4 Hanson Institute, Adelaide SA 5000, Australia

Address correspondence to Paul G. Ekert, The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Tel.: 61-3-9345-2548. Fax: 61-3-9347-0852. email: ekert{at}wehi.edu.au

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.

Key Words: apoptosis; growth factor; caspases; Apaf-1; Bcl-2

The online version of this article contains supplemental material.

Abbreviation used in this paper: PI, propidium iodide.


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