Suppression of calcium release from inositol 1,4,5-trisphosphate-sensitive stores mediates the anti-apoptotic function of nuclear factor-κB

The activation of the transcription factor nuclear factor-kappa B (NF-kappa B) 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-kappa B on calcium signaling that accounts for its anti-apoptotic function. Embryonic fibroblasts lacking the transactivating subunit of NF-kappa B 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-kappa B and are increased when NF-kappa B activity is suppressed. The selective antagonism of IP3 receptors blocks apoptosis in RelA-deficient cells, whereas activation of NF-kappa B 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-kappa B-mediated cell survival signaling.