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J. Biol. Chem., Vol. 280, Issue 23, 22287-22296, June 10, 2005

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Suppression of Calcium Release from Inositol 1,4,5-Trisphosphate-sensitive Stores Mediates the Anti-apoptotic Function of Nuclear Factor-B^*

Simonetta Camandola, Roy G. Cutler, Devin S. Gary, Ollivier Milhavet, and Mark P. Mattson¶

From the Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland 21224 and ^¶Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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

Received for publication, September 22, 2004 , and in revised form, March 22, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Neurosciences, National Institute on Aging, GRC 4F01, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8617; Fax: 410-558-8386; E-mail: camandolasi{at}grc.nia.nih.gov.

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