The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites.
Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF-kappa B. Such homodimers are abundant for example in nuclei of unstimulated primary T cells. Here we extend the model and provide new evidence which fulfills a number of predictions. (i) Bcl-3 preferentially targets p50 homodimers over NF-kappa B heterodimers since the homodimers are completely dissociated from kappa B sites at concentrations of Bcl-3 which do not affect NF-kappa B. (ii) Select kappa B sites associate very strongly and stably with p50 homodimers, completely preventing binding by NF-kappa B. Such kappa B sites are likely candidates for regulation by p50 homodimers and Bcl-3. (iii) Bcl-3 and p50 can be co-localized in the nucleus, a requirement for active removal of homodimers from their binding sites in vivo. (iv) The ankyrin repeat domain of Bcl-3 is sufficient for the reversal of p50 homodimer-mediated inhibition, correlating with the ability of this domain alone to inhibit p50 binding to kappa B sites in vitro. Our data support the model that induction of nuclear Bcl-3 may be required during cellular stimulation to actively remove stably bound p50 homodimers from certain kappa B sites in order to allow transactivating NF-kappa B complexes to engage. This exact mechanism is demonstrated with in vitro experiments.
Franzoso
G
G
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Bours
V
V
Azarenko
V
V
Park
S
S
Tomita-Yamaguchi
M
M
Kanno
T
T
Brown
K
K
Siebenlist
U
U
D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D000081242:B-Cell Lymphoma 3 Protein; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D014157:Transcription Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D017487:Ankyrins; D000081242:B-Cell Lymphoma 3 Protein; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D004247:DNA