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. Footnotes Address all correspondence to Clark W. Distelhorst, Department of Medicine, Biomedical Research Building Room 329, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4937. Tel.: (216) 368-1176. Fax: (216) 368-1166. e-mail: email@example.com 1. Abbreviation used in this paper : TG, thapsigargin. Submitted: 26 February 1997 Revision received 14 May 1997
The Journal of Cell Biology – Rockefeller University Press
Published: Sep 22, 1997
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