TY - JOUR
T1 - Suppression of calcium release from inositol 1,4,5-trisphosphate-sensitive stores mediates the anti-apoptotic function of nuclear factor-κB
AU - Camandola, Simonetta
AU - Cutler, Roy G.
AU - Gary, Devin S.
AU - Milhavet, Ollivier
AU - Mattson, Mark P.
PY - 2005/6/10
Y1 - 2005/6/10
N2 - The activation of the transcription factor nuclear factor-κB (NF-κB) by growth factors, cytokines, and cellular stress can prevent apoptosis, but the underlying mechanism is unknown. Here we provide evidence for an action of NF-κB on calcium signaling that accounts for its anti-apoptotic function. Embryonic fibroblasts lacking the transactivating subunit of NF-κB RelA (p65) exhibit enhanced inositol 1,4,5-trisphosphate (IP3) receptor-mediated calcium release and increased sensitivity to apoptosis, which are restored upon re-expression of RelA. The size of the endoplasmic reticulum (ER) calcium pool and the number of IP3 receptors per cell are decreased in response to stimuli that activate NF-κB and are increased when NF-κB activity is suppressed. The selective antagonism of IP3 receptors blocks apoptosis in RelA-deficient cells, whereas activation of NF-κB in normal cells leads to decreased levels of the type 1 IP3 receptor and decreased calcium release. Overexpression of Bcl-2 normalizes ER calcium homeostasis and prevents calcium-mediated apoptosis in RelA-deficient cells. These findings establish an ER calcium channel as a pivotal target for NF-κB-mediated cell survival signaling.
AB - The activation of the transcription factor nuclear factor-κB (NF-κB) by growth factors, cytokines, and cellular stress can prevent apoptosis, but the underlying mechanism is unknown. Here we provide evidence for an action of NF-κB on calcium signaling that accounts for its anti-apoptotic function. Embryonic fibroblasts lacking the transactivating subunit of NF-κB RelA (p65) exhibit enhanced inositol 1,4,5-trisphosphate (IP3) receptor-mediated calcium release and increased sensitivity to apoptosis, which are restored upon re-expression of RelA. The size of the endoplasmic reticulum (ER) calcium pool and the number of IP3 receptors per cell are decreased in response to stimuli that activate NF-κB and are increased when NF-κB activity is suppressed. The selective antagonism of IP3 receptors blocks apoptosis in RelA-deficient cells, whereas activation of NF-κB in normal cells leads to decreased levels of the type 1 IP3 receptor and decreased calcium release. Overexpression of Bcl-2 normalizes ER calcium homeostasis and prevents calcium-mediated apoptosis in RelA-deficient cells. These findings establish an ER calcium channel as a pivotal target for NF-κB-mediated cell survival signaling.
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U2 - 10.1074/jbc.M410923200
DO - 10.1074/jbc.M410923200
M3 - Article
C2 - 15814613
AN - SCOPUS:20444457553
SN - 0021-9258
VL - 280
SP - 22287
EP - 22296
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 23
ER -