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Farley, Nicholas R.

Cell and Molecular Biology Program

2006

M.S.

The FAS death receptor is a critical mediator of cell death signals for many cell types, including T cells. Binding of FAS ligand (FAS-L) to the FAS receptor triggers multiple signaling events, for example, the activation of caspases, nuclear factor kappa B (NFKB), and the mitogen-activated protein kinases (MAPKs), specifically c-Jun NH₂-terminal kinase (JNK) and p38 MAPK. The final outcome of FAS signaling is due to the combined balance of proapoptotic signals (ie: caspases) and anti-apoptotic signals (ie: NFKB). The p38 MAPK pathway has been linked to cell death through other stress stimuli (ultraviolet radiation, osmotic stress, etc) or death signals (TNFR signaling). Although the activation of p38 MAPK through FAS is well established, the contribution of p38 MAPK activity to FAS-induced apoptosis remains unclear. Here we demonstrate that the activation of p38 MAPK is essential for the induction of apoptosis through FAS in CD8⁺ T cells, p38 MAPK is able to phosphorylate the anti-apoptotic proteins Bcl-2 and Bcl-XL, and prevent their translocation to the mitochondria. A localized deficiency of anti-apoptotic factors at the mitochondrial surface allow for cytochrome C release and caspase activation. Thus, p38 MAPK is a critical link between FAS and the mitochondrial death pathway that is required for apoptosis of CD8⁺ T cells.