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.