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 (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.
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Departments of Medicine and Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Lam
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McCormick
T S
TS
Distelhorst
C W
CW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000737:chemistry* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology*; D008223:Lymphoma; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000201:enzymology
D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium