Maintenance of Calcium Homeostasis in the Endoplasmic Reticulum by Bcl-2

The oncogene bcl-2 encodes a 26-kD protein localized to intracellular membranes, including the ER, mitochondria, and perinuclear membrane, but its mechanism of action is unknown. We have been investigating the hypothesis that Bcl-2 regulates the movement of calcium ions (Ca(2+)) through the ER membrane. Earlier findings in this laboratory indicated that Bcl-2 reduces Ca(2+) efflux from the ER lumen in WEHI7.2 lymphoma cells treated with the Ca(2+)-ATPase inhibitor thapsigargin (TG) but does not prevent capacitative entry of extracellular calcium. In this report, we show that sustained elevation of cytosolic Ca(2+) due to capacitative entry is not required for induction of apoptosis by TG, suggesting that ER calcium pool depletion may trigger apoptosis. Bcl-2 overexpression maintains Ca(2+) uptake in the ER of TG-treated cells and prevents a TG-imposed delay in intralumenal processing of the endogenous glycoprotein cathepsin D. Also, Bcl-2 overexpression preserves the ER Ca(2+) pool in untreated cells when extracellular Ca(2+) is low. However, low extracellular Ca(2+) reduces the antiapoptotic action of Bcl-2, suggesting that cytosolic Ca(2+) elevation due to capacitative entry may be required for optimal ER pool filling and apoptosis inhibition by Bcl-2. In summary, the findings suggest that Bcl-2 maintains Ca(2+) homeostasis within the ER, thereby inhibiting apoptosis induction by TG.