Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

Abstract

The transcription factors NF-B/Rel play a key role in regulating a diverse array of genes involved in cell growth, differentiation, and adaptive responses to environmental factors that are cell-and stimulus-specific (1). In the central nervous system, NF-B/Rel proteins are ubiquitously expressed in neurons and glia (2, 3) where, in addition to regulating physiological processes, they participate in pathological events associated with neurodegeneration (3, 4). Increased NF-B/Rel levels have been observed in the dying neurons of brains exposed to trauma and ischemia (5-8) as well as in brains of patients with Alzheimer's disease and Parkinson's disease (9 -11). Whether NF-B/Rel participates in a neurodegenerative program or otherwise in a neuroprotective process by increasing neuronal resistance to various noxae is still debated. Although many studies support the antiapoptotic effects of NF-B/Rel in cultured neurons (12-15), conflicting evidence has emerged from experimental models of pathological conditions affecting adult neurons. For example, some studies showed that NF-B/Rel mediates the neuroprotection elicited by the tumor necrosis factor in hippocampal cells (16,17) and promotes neuronal resistance to excitotoxicity (18) and ␤-amyloid-induced apoptosis (19). Other studies demonstrated that the activation of NF-B/Rel triggers neuronal degeneration after cerebral ischemia (6, 8) and mediates the glutamate-activated cell death program during excitotoxic insults to central neurons (4,20,21).NF-B/Rel proteins are a family of transcription factors composed of several members, including p50, p52, p65/RelA, RelB, and c-Rel, that form homo-and heterodimers capable of transmitting receptor signals to the nucleus (3,22). In resting cells, NF-B/Rel factors are retained in the cytoplasm by association with the inhibitory IB proteins. In stimulated cells, IB is phosphorylated and degradated, thus allowing the release and nuclear translocation of NF-B dimers. Recently, a more complex regulation of NF-B/Rel activation that involves modulatory phosphorylations has been emerging. The phosphorylation of NF-B/Rel components may operate to optimize their DNA binding and transcriptional activities, as well as functional interaction with coactivators (23). The diverse phenotypes of different NF-B/Rel knockout mice suggest that each NF-B/ Rel member serves unique physiological roles in vivo, presumably via the regulation of distinct sets of target genes. Thus, the opposite regulation of neuron survival by NF-B/Rel may very well depend on the activation of a distinct combination of subunits, resulting in the differential regulation of target genes and the induction of diverse genetic programs that dictate the cell fate (24 -26).In this study, we investigated the contribution of different NF-B/Rel proteins to the cell survival of brain neurons exposed to IL-1␤ 1 and glutamate, two common activators of NF-* This work was supported by grants from the Consiglio Nazionale delle Richerche (CNR 2000), the Italian Health Ministry, the Ital...

Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

“…Thus, interference with the NF-B pathway at various levels reveals a deleterious role of NF-B in cerebral ischemia, which is in apparent contrast to what has been found in other paradigms. There is ample evidence that NF-B inhibits apoptosis in tumor cells, hepatocytes, and many other cell types, including neurons (Pizzi et al, 2002;Fridmacher et al, 2003;Tarabin and Schwaninger, 2004). In stroke models, however, protective effects of NF-B, which may be mediated by c-Rel (Pizzi et al, 2002), are overrun by the deleterious action of p50 and RelA.…”

“…NF-B consists of the five subunits p50, p52, RelA, c-Rel, and RelB. Surprisingly, in some paradigms, NF-B promotes apoptosis (Kaltschmidt et al, 2000(Kaltschmidt et al, , 2002Pizzi et al, 2002). In a mouse model of stroke, NF-B was associated with neurodegeneration because germline deletion of the gene for the NF-B subunit p50 reduced the infarct size (Schneider et al, 1999;Nurmi et al, 2004).…”

“…Indeed, functional diversity is suggested by the unique phenotypes of knock-out mouse lines (Li and Verma, 2002). Recent evidence has shown that RelA exerts a proapoptotic and c-Rel an antiapoptotic effect in neurons (Pizzi et al, 2002(Pizzi et al, , 2005.…”

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

“…Accordingly, topoisomerase II inhibitors that intercalate into the DNA such as doxorubicin, daunorubicin, and mitoxantrone trigger NF-kB activation before the induction of apoptosis, and NF-kB inhibition significantly reduces apoptosis (24). In addition, a proapoptotic function of NF-kB has been described in several systems of neuronal cell death, for example, induced by ischemia, glutamate, betulinic acid, or NMDA receptors stimulation (25,(33)(34)(35)(36).…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Aside from a role in promoting neuronal survival (Pizzi et al, 2002(Pizzi et al, , 2005, c-Rel has also been implicated in long-term memory (LTM) formation. Consolidation of LTM requires N-methyl-D-aspartate receptor-dependent changes in gene expression.…”