DT40 cells lacking the Ca 2+ -binding protein annexin 5 are resistant to Ca 2+ -dependent apoptosis

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Abstract
Annexins are widely expressed Ca 2+ -dependent phospholipid-binding proteins with poorly understood physiological roles. Proposed functions include Ca 2+ channel activity and vesicle trafficking, but neither have been proven in vivo . Here we used targeted gene disruption to generate B-lymphocytes lacking annexin 5 (Anx5) expression and show that this results in reduced susceptibility to a range of apoptotic stimuli. By comparison B-lymphocytes lacking annexin 2 (Anx2) showed no such resistance, providing evidence that this effect is specific to loss of Anx5. The defect in the ANX5 −/− cells occurs early in the apoptotic program before nuclear condensation, caspase 3 activation, and cell shrinkage, but downstream of an initial Ca 2+ influx. Only UVA/B irradiation induced similar levels of apoptosis in wild-type and ANX5 −/− cells. Unexpectedly, ANX5 −/− cells permeabilized in vitro also failed to release mitochondrial cytochrome C, suggesting a possible mechanism for their resistance to apoptosis. These findings demonstrate a role for Anx5 in determining the susceptibility of B-lymphocytes to apoptosis.