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

Abstract

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 (Ca2+) through the ER membrane. Earlier findings in this laboratory indicated that Bcl-2 reduces Ca2+ efflux from the ER lumen in WEHI7.2 lymphoma cells treated with the Ca2+-ATPase inhibitor thapsigargin (TG) but does not prevent capacitative entry of extracellular calcium. In this report, we show that sustained elevation of cytosolic Ca2+ 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 Ca2+ 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 Ca2+ pool in untreated cells when extracellular Ca2+ is low. However, low extracellular Ca2+ reduces the antiapoptotic action of Bcl-2, suggesting that cytosolic Ca2+ 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 Ca2+ homeostasis within the ER, thereby inhibiting apoptosis induction by TG.

Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1

“…If the cell is not capable of maintaining an adequate level of Ca 2+ in intracellular stores, many cellular functions including posttranslational modifications of recombinant proteins will be abnormal. Store depletion may elicit problematic protein trafficking, sarcoplasmic reticulum (SR) stress (Cudna and Dickson 2003), growth arrest (Short et al 1993), and apoptosis (He et al 1997) caused by the resulting disturbance of posttranslational protein modification. Ca 2+ influx through SOCE involves keeping a sustained high Ca 2+ concentration in the Ca 2+ stores and refilling the SR when it releases Ca 2+ .…”

Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2

“…Third, Bcl-2 may modulate ER membrane permeability by either forming an ion channel or regulating ERbased channels or pumps such as the IP 3 -receptor calcium channel or the Ca 2+ ATPase pump (SERCA) (Berridge et al, 1998). Bcl-2 can interact with SERCA and either maintain calcium uptake into the ER or reduce calcium e ux of the ER in cells treated with the SERCA inhibitor thapsigargin (Kuo et al, 1998;He et al, 1997). Finally, we propose that Bcl-2 may act on any intracellular membrane to sequester yet unknown cytoplasmic activators of cytochrome c release.…”

Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

“…Indeed, in the same years a number of reports appeared which did not support the notion that Bcl-2 reduces ER Ca 2 þ levels. The largest body of work was carried out by the group of Distelhorst 19,41,[53][54][55] that in recent papers reported that the size of ionomycin-releasable intracellular Ca 2 þ pools was the same in controls and Bcl-2-expressing cells. 56 Work by other groups support this view.…”