Apaf-1 and caspase-9 are required for cytokine withdrawal-induced apoptosis of mast cells but dispensable for their functional and clonogenic death
- Author(s)
- Marsden, VS; Kaufmann, T; O'Reilly, LA; Adams, JM; Strasser, A;
- Details
- Publication Year 2006-03-01,Volume 107,Issue #5,Page 1872-1877
- Journal Title
- BLOOD
- Publication Type
- Journal Article
- Abstract
- Cytokines promote survival of mast cells by inhibiting apoptotic pathways regulated by the Bcl-2 protein family. We previously showed that lymphocyte apoptosis can proceed via a Bcl-2-inhibitable pathway independent of the canonical initiator caspase, caspase-9, and its adaptor, Apaf-1. Here we report that mast cells lacking caspase-9 or Apaf-1 are refractory to apoptosis after cytotoxic insults but still lose effector function and ability to proliferate. In response to cytokine deprivation or DNA damage, fetal liver-derived mast cells lacking Apaf-1 or caspase-9 failed to undergo apoptosis. Nevertheless, the cytokine-starved cells were not functionally alive, because, unlike those overexpressing Bcl-2, they could not degranulate on Fc epsilon receptor stimulation or resume proliferation on re-addition of cytokine. Furthermore, mast cells lacking Apaf-1 or caspase-9 had no survival advantage over wild-type counterparts in vivo. These results indicate that the Apaf-1/caspase-9-independent apoptotic pathway observed in lymphocytes is ineffective in cytokine-deprived mast cells. However, although Apaf-1 and caspase-9 are essential for mast cell apoptosis, neither is required for the functional or clonogenic death of the cells, which may be due to mitochondrial dysfunction.
- Publisher
- AMER SOC HEMATOLOGY
- Keywords
- BCL-X-L; KIT-LIGAND; PROLIFERATION; ACTIVATION; EXPRESSION; CLEAVAGE; SURVIVAL; FAMILY; BIM
- Publisher's Version
- https://doi.org/10.1182/blood-2005-05-2160
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2006-03-01 12:00:00