Reduced loading of intracellular Ca(2+) stores and downregulation of capacitative Ca(2+) influx in Bcl-2-overexpressing cells.
The mechanism of action of the oncogene bcl-2, a key regulator of the apoptotic process, is still debated. We have employed organelle-targeted chimeras of the Ca(2+)-sensitive photoprotein, aequorin, to investigate in detail the effect of Bcl-2 overexpression on intracellular Ca(2+) homeostasis. In the ER and the Golgi apparatus, Bcl-2 overexpression increases the Ca(2+) leak (while leaving Ca(2+) accumulation unaffected), hence reducing the steady-state [Ca(2+)] levels. As a direct consequence, the [Ca(2+)] increases caused by inositol 1,4,5 trisphosphate (IP3)-generating agonists were reduced in amplitude in both the cytosol and the mitochondria. Bcl-2 overexpression also reduced the rate of Ca(2+) influx activated by Ca(2+) store depletion, possibly by an adaptive downregulation of this pathway. By interfering with Ca(2+)-dependent events at multiple intracellular sites, these effects of Bcl-2 on intracellular Ca(2+) homeostasis may contribute to the protective role of this oncogene against programmed cell death.
Pinton
P
P
Department of Experimental and Diagnostic Medicine, Section of General Pathology, 44100 Ferrara, Italy.
Ferrari
D
D
Magalhães
P
P
Schulze-Osthoff
K
K
Di Virgilio
F
F
Pozzan
T
T
Rizzuto
R
R
D000255:Adenosine Triphosphate / Q000494:pharmacology; D020346:Aquaporins / Q000235:genetics; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016257:Fura-2; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
D020346:Aquaporins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D002118:Calcium; D016257:Fura-2