Bcl-2 inhibits c-fos induction by calcium.
Transient elevation of cytosolic Ca2+ induces the expression of a variety of genes involved in cell growth and transformation, including the early response gene c-fos. Previously, we reported that Bcl-2 inhibits the transient elevation of cytosolic Ca2+ induced by thapsigargin (TG), a selective inhibitor of the endoplasmic reticulum-associated Ca2+-ATPase. Therefore, to determine if the effect of Bcl-2 on cytosolic Ca2+ elevation modulates Ca2+ signaling, we investigated the induction of c-fos by TG in WEHI7.2 mouse lymphoma cells, control transfectants (WEHI7.2-neo), and transfectants that stably express a high level of Bcl-2 (W.Hb12 and W.Hb15). TG induced 20-fold elevation of c-fos mRNA in WEHI7.2 and WEHI7.2-neo cells, but c-fos mRNA induction by TG was only fivefold in W.Hb12 and W.Hb15 cells. In contrast, phorbol 12-myristate acetate induced marked c-fos mRNA elevation in both WEHI7.2 and W.Hb12 cells, indicating that the inhibitory effect of Bcl-2 is selective for induction of c-fos by Ca2+. To measure c-fos promoter activity, WEHI7.2 and W.Hb12 cells were transiently transfected with a c-fos promoter-luciferase reporter plasmid. TG induced c-fos promoter activity in WEHI7.2 cells, but not in W.Hb12 cells. In WEHI7.2 cells, the signal for c-fos induction by TG was cytosolic Ca2+ elevation, as the increase in both c-fos mRNA level and promoter activity were prevented by lowering extracellular Ca2+ concentration, a condition that inhibits cytosolic Ca2+ elevation by reducing the TG-mobilizable Ca2+ pool. In summary, the findings indicate that Bcl-2 regulates Ca2+ signaling.
Qi
X M
XM
Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Simonson
M
M
Distelhorst
C W
CW
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D008223:Lymphoma; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D019253:Proto-Oncogene Proteins c-bcl-2; D019284:Thapsigargin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium