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

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 fac...

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Bibliographic Details
Published in:The Journal of cell biology 2004-06, Vol.165 (6), p.835-842
Main Authors: Ekert, Paul G., Read, Stuart H., Silke, John, Marsden, Vanessa S., Kaufmann, Hitto, Hawkins, Christine J., Gerl, Robert, Kumar, Sharad, Vaux, David L.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - physiology
Apoptotic Protease-Activating Factor 1
Cancer
Caspase 9
Caspases - deficiency
Caspases - genetics
Caspases - physiology
Cell cycle
Cell death
Cell growth
Cell Line
Cell lines
Cell Survival - drug effects
Cell Survival - physiology
Cells
Cellular biology
Cultured cells
Cytochromes
Cytochromes c - analysis
Drug therapy
Flow Cytometry
Gene Deletion
Interleukin-3 - pharmacology
Lymphocytes
Memory interference
Mice
Mice, Knockout
Proteins
Proteins - genetics
Proteins - physiology
T lymphocytes
Tumor Cells, Cultured
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200312031