NF-κB-inducible BCL-3 Expression Is an Autoregulatory Loop Controlling Nuclear p50/NF-κB1 Residence*

By A. Brasier, Muping Lu, T. Hai, Ying Lu, I. Boldogh. Journal of Biological Chemistry, 2001

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NF-κB is a transcription factor whose nuclear residence is controlled by IκB family members. In the NF-κB-IκB autoregulatory loop, activated (nuclear) Rel A·NF-κB1 induces the resynthesis of IκBα recapturing nuclear Rel A back into the cytoplasm within 1 h of stimulation. In contrast, NF-κB1 subunits redistribute more slowly into the cytoplasm (from 6 to 12 h). Here we examine the role of inducible cytoplasmic BCL-3 expression in terminating nuclear NF-κB1. Although BCL-3 is a nuclear protein in B lymphocytes, surprisingly, BCL-3 is primarily a cytoplasmic protein in HepG2 cells. Cytoplasmic BCL-3 abundance is induced 6–12 h after tumor necrosis factor-α stimulation where it complexes with NF-κB1 homodimers. Moreover, BCL-3 mRNA and protein expression are induced by NF-κB-activating agents. Two observations are interpreted to indicate that bcl-3 is transactivated by NF-κB/Rel A: 1) expression of a dominant negative NF-κB inhibitor blocks tumor necrosis factor-α-induced BCL-3 expression and 2) expression of constitutively active Rel A is sufficient to induce BCL-3 expression. In gene transfer studies, we identify two high affinity NF-κB-binding sites, κB1 (located at −872 to −861 nucleotides) and κB2 (−106 to −96 nucleotides), and although both bind with high affinity to Rel A, only κB2 is required for NF-κB-dependent induction of the native BCL-3 promoter. Down-regulation of BCL-3 induction results in prolonged, enhanced NF-κB1 binding and increased NF-κB-dependent transcription. Together, these data suggest the presence of an NF-κB-BCL-3 autoregulatory loop important in terminating NF-κB1 action and that individual NF-κB isoforms are actively terminated through coordinate induction of inhibitory IκB molecules to restore cellular homeostasis.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6db7ed5980c63433f1537c8c6a78c5af779eb821

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