Members of the bcl-2 gene family encode proteins that function either to promote or to inhibit apoptosis. Despite numerous efforts, the mechanism of action of Bcl-2, an anti-apoptotic protein, is still not clear. In particular, the relation between Bcl-2 and the endoplasmic reticulum (ER) calcium store is not well-understood. In the present work, we examined the effect of Bcl-2 on the ER store. We demonstrate that overexpression of Bcl-2 in breast epithelial cells modulates ER store by upregulating calcium pump (SERCA) expression without affecting the release channel (IP 3 R). The steady state levels of SERCA2 mRNA and protein were both increased in Bcl-2 expression clones. The increase in SERCA2 protein leads to accelerated calcium uptake and enhanced Ca 2+ loading. In addition, we also show the detection of intracellular interaction between Bcl-2 and SERCA molecules by co-immunoprecipitation. Since high lumenal Ca 2+ concentration of ER is essential for normal cell functions, the results suggest that Bcl-2 preserves the ER Ca 2+ store by upregulating SERCA gene expression as well as by a possible interaction with the pump.