Reduced loading of intracellular Ca2+ stores and downregulation of capacitative Ca2+ influx in Bcl-2-overexpressing cells

The mechanism of action of the oncogene bcl-2, a key regulator of the apopt otic process, is still debated. We have employed organelle-targeted chimera s of the Ca2+-sensitive photoprotein, aequorin, to investigate in detail th e effect of Bcl-2 overexpression on intracellular Ca2+ homeostasis. In the ER and the Golgi apparatus, Bcl-2 overexpression increases the Ca2+ leak (w hile leaving Ca2+ accumulation unaffected), hence reducing the steady-state [Ca2+] levels. As a direct consequence, the [Ca2+] increases caused by ino sitol 1,4,5 trisphosphate (IP3)-generating agonists were reduced in amplitu de in both the cytosol and the mitochondria. Bcl-2 overexpression also redu ced the rate of Ca2+ in flux activated by Ca2+ store depletion, possibly by an adaptive downregulation of this pathway. By interfering with Ca2+-depen dent events at multiple intracellular sites, these effects of Bcl-2 on intr acellular Ca2+ homeostasis may contribute to the protective role of this on cogene against programed cell death.