NF-kappaB/p50 and NF-kappaB/c-Rel differentially regulate the activity of the 3'alphaE-hsl,2 enhancer in normal murine B cells in an activation-dependent manner.
The enhancer complex located 3' to the C(H)alpha gene in the IgH locus (3alphaE) may regulate B cell function through its ability to act as a locus control region. Multiple, functionally relevant NF-kappaB binding sites are located within the 3'alphaE. NF-kappaB subunits, especially p50 and c-Rel, have also been shown to play critical and differential roles in regulating B cell proliferation, Ig secretion, germline C(H) transcription and Ig class switching. Thus, NF-kappaB could regulate B cell function in part through modulation of 3'alphaE activity. In this study we determined whether p50 and/or c-Rel regulate 3'alphaE activity in normal murine B cells and whether this depends on the nature of the B cell activator. For this purpose, we crossed p50- and c-Rel-deficient mice with mice that are transgenic for a 3'alphaE-hsl,2-human beta-globin reporter gene, and established p50(-/-) or c-Rel(-/-) mice homozygous for the enhancer transgene. We show, using optimal stimulating conditions, that p50 selectively augments 3'alpha E-hsl,2 activity in lipopolysaccharide-activated B cells, whereas c-Rel is required for optimal 3'alphaE-hs1,2 induction in B cells activated through CD40.
Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
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Zelazowski
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Shen
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Snapper
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology; D003433:Crosses, Genetic; D003907:Dexamethasone / Q000494:pharmacology; D019281:Dimerization; D004742:Enhancer Elements, Genetic; D005803:Genes, Immunoglobulin; D017930:Genes, Reporter; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology
D019013:CD40 Antigens; D007143:Immunoglobulin Heavy Chains; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand; D015847:Interleukin-4; D003907:Dexamethasone; D005914:Globins