Influx In Bcl-2–Overexpressing Cells

The mechanism of action of the oncogene bcl-2 , a key regulator of the apoptotic process, is still debated. We have employed organelle-targeted chimeras of the Ca 2 1 -sensitive photoprotein, aequorin, to investigate in detail the effect of Bcl-2 overexpression on intracellular Ca 2 1 homeostasis. In the ER and the Golgi apparatus, Bcl-2 overexpression increases the Ca 2 1 leak (while leaving Ca 2 1 accumulation unaffected), hence reducing the steady-state [Ca 2 1 ] levels. As a direct consequence, the [Ca 2 1 ] increases caused by inositol 1,4,5 trisphosphate (IP3)-generating agonists were reduced in amplitude in both the cytosol and the mitochondria. Bcl-2 overexpression also reduced the rate of Ca 2 1 influx activated by Ca 2 1 store depletion, possibly by an adaptive downregulation of this pathway. By interfering with Ca 2 1 -dependent events at multiple intracellular sites, these effects of Bcl-2 on intracellular Ca 2 1 homeostasis may contribute to the protective role of this oncogene against programed cell death.