NF-kappaB p50/RelA and c-Rel-containing dimers: opposite regulators of neuron vulnerability to ischaemia.
Diverse nuclear factor-kappaB subunits mediate opposite effects of extracellular signals on neuron survival. While RelA is activated by neurotoxic agents, c-Rel drives neuroprotective effects. In brain ischaemia RelA and p50 factors rapidly activate, but how they associate with c-Rel to form active dimers and contribute to the changes in diverse dimer activation for neuron susceptibility is unknown. We show that in both cortical neurons exposed to oxygen glucose deprivation (OGD) and mice subjected to brain ischaemia, activation of p50/RelA was associated with inhibition of c-Rel/RelA dimer and no change p50/c-Rel. Targeting c-Rel and RelA expression revealed that c-Rel dimers reduced while p50/RelA enhanced neuronal susceptibility to anoxia. Activation of p50/RelA complex is known to induce the pro-apoptotic Bim and Noxa genes. We now show that c-Rel-containing dimers, p50/c-Rel and RelA/c-Rel, but not p50/RelA, promoted Bcl-xL transcription. Accordingly, the OGD exposure induced Bim, but reduced Bcl-xL promoter activity and decreased the content of endogenous Bcl-xL protein. These findings demonstrate that within the same neuronal cell, the balance between activation of p50/RelA and c-Rel-containing complexes fine tunes the threshold of neuron vulnerability to the ischaemic insult. Selective targeting of different dimers will unravel new approaches to limit ischaemia-associated apoptosis.
Sarnico
Ilenia
I
Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences & Biotechnologies, School of Medicine, University of Brescia, Viale Europa 11, Brescia, Italy.
Lanzillotta
Annamaria
A
Boroni
Flora
F
Benarese
Marina
M
Alghisi
Manuela
M
Schwaninger
Markus
M
Inta
Ioana
I
Battistin
Leontino
L
Spano
PierFranco
P
Pizzi
Marina
M
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D006801:Humans; D000860:Hypoxia; D047468:Immunoprecipitation / Q000379:methods; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000502:physiology*; D014162:Transfection / Q000379:methods; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D051020:bcl-X Protein; D005947:Glucose