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PMID:8022822

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Citation

Lam, M, Dubyak, G, Chen, L, Nuñez, G, Miesfeld, RL and Distelhorst, CW (1994) Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc. Natl. Acad. Sci. U.S.A. 91:6569-73

Abstract

BCL-2 is a 26-kDa integral membrane protein that represses apoptosis by an unknown mechanism. Recent findings indicate that Ca2+ release from the endoplasmic reticulum (ER) mediates apoptosis in mouse lymphoma cells. In view of growing evidence that BCL-2 localizes to the ER, as well as mitochondria and the perinuclear membrane, we investigated the possibility that BCL-2 represses apoptosis by regulating Ca2+ fluxes through the ER membrane. A cDNA encoding BCL-2 was introduced into WEHI7.2 cells and two subclones, W.Hb12 and W.Hb13, which express high and low levels of BCL-2 mRNA and protein, respectively, were isolated. WEHI7.2 cells underwent apoptosis in response to treatment with the glucocorticoid hormone dexamethasone, whereas W.Hb12 and W.Hb13 cells were protected from apoptosis, revealing a direct relationship between the level of BCL-2 expression and the degree of protection. Significantly, BCL-2 also blocked induction of apoptosis by thapsigargin (TG), a highly specific inhibitor of the ER-associated Ca2+ pump. TG completely inhibited ER Ca2+ pumping in both WEHI7.2 and W.Hb12 cells, but the release of Ca2+ into the cytosol after inhibition of ER Ca2+ pumping was significantly less in W.Hb12 cells than in WEHI7.2 cells, indicating that BCL-2 reduces Ca2+ efflux through the ER membrane. By reducing ER Ca2+ efflux, BCL-2 interfered with a signal for "capacitative" entry of extracellular Ca2+, preventing a sustained increase of cytosolic Ca2+ in TG-treated cells. These findings suggest that BCL-2 either directly or indirectly regulates the flux of Ca2+ across the ER membrane, thereby abrogating Ca2+ signaling of apoptosis.

Links

PubMed PMC44244

Keywords

Apoptosis/physiology; Calcium/metabolism; Calcium-Transporting ATPases/antagonists & inhibitors; Calcium-Transporting ATPases/metabolism; Cell Line; Cell Membrane Permeability; Cell Survival/drug effects; Clone Cells; Dexamethasone/pharmacology; Digitonin; Endoplasmic Reticulum/metabolism; GTP-Binding Proteins/metabolism; Humans; Kinetics; Proto-Oncogene Proteins/biosynthesis; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogenes; RNA, Messenger/biosynthesis; Terpenes/pharmacology; Thapsigargin; Time Factors; Transfection

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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