Abstract
The activation of the transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB on calcium signaling that accounts for its anti-apoptotic function. Embryonic fibroblasts lacking the transactivating subunit of NF-kappaB RelA (p65) exhibit enhanced inositol 1,4,5-trisphosphate (IP(3)) 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 IP(3) receptors per cell are decreased in response to stimuli that activate NF-kappaB and are increased when NF-kappaB activity is suppressed. The selective antagonism of IP(3) receptors blocks apoptosis in RelA-deficient cells, whereas activation of NF-kappaB in normal cells leads to decreased levels of the type 1 IP(3) 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-kappaB-mediated cell survival signaling.
Highlights
Established, several candidates have been identified including Bcl-2 family members [6], manganese superoxide dismutase [5], and members of the inhibitor of apoptosis protein family [7]
These data indicate that the lack of nuclear factor-B (NF-B) activity as the result of RelA deletion causes a profound alteration of endoplasmic reticulum (ER) calcium signaling that involves increased sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) activity, ER calcium uptake, and IP3-mediated calcium release and that this alteration can be counteracted by Bcl-2
Abnormalities in ER calcium release have been implicated in diseases that involve aberrant apoptosis
Summary
Vol 280, No 23, Issue of June 10, pp. 22287–22296, 2005 Printed in U.S.A. Suppression of Calcium Release from Inositol 1,4,5-Trisphosphatesensitive Stores Mediates the Anti-apoptotic Function of Nuclear Factor-B*. Overexpression of Bcl-2 normalizes ER calcium homeostasis and prevents calciummediated apoptosis in RelA-deficient cells. These findings establish an ER calcium channel as a pivotal target for NF-B-mediated cell survival signaling. Established, several candidates have been identified including Bcl-2 family members [6], manganese superoxide dismutase [5], and members of the inhibitor of apoptosis protein family [7] These proteins may block the apoptotic process by stabilizing mitochondrial membranes, decreasing oxyradical levels, and inhibiting caspases. It was recently reported that activation of inositol 1,4,5-trisphosphate (IP3) receptors regulates NF-B activity [25], suggesting a possible role for NF-B in modulation of cell survival/death decisions under conditions in which ER calcium release plays a role. We identify suppression of calcium release through IP3 receptors as a key mechanism whereby NF-B prevents apoptosis
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