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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.

Original publication

DOI

10.1083/jcb.200312031

Type

Journal article

Journal

J Cell Biol

Publication Date

21/06/2004

Volume

165

Pages

835 - 842

Keywords

Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, Caspase 9, Caspases, Cell Line, Cell Survival, Cytochromes c, Flow Cytometry, Gene Deletion, Interleukin-3, Mice, Mice, Knockout, Proteins, Tumor Cells, Cultured