Suppression of calcium release from inositol 1,4,5-trisphosphate-sensitive stores mediates the anti-apoptotic function of nuclear factor-kappaB.
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.
Camandola
Simonetta
S
Laboratory of Neurosciences, National Institute on Aging/NIH, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. camandolasi@grc.nia.nih.gov
Cutler
Roy G
RG
Gary
Devin S
DS
Milhavet
Ollivier
O
Mattson
Mark P
MP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002470:Cell Survival; D002518:Ceramides / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008861:Microsomes / Q000378:metabolism; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA; D015533:Transcriptional Activation
D015220:Calcium Channels; D002518:Ceramides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D004247:DNA; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium