Nuclear factor-κB dimer exchange promotes a p21waf1/cip1 superinduction response in human T leukemic cells

Abstract

The nuclear factor-κB (NF-κB)/Rel transcription factors are recognized as critical apoptosis regulators. We reported previously that NF-κB contributes to chemoresistance of CEM human T leukemic cells in part through its ability to induce p21waf1/ciP1. Here, we provide evidence that sequential NF-κB-activating signals induce heightened NF-κB DNA binding and p21waf1/ciP1 induction in CEM and additional T leukemic cell lines. This response arises from exceedingly low basal expression of the p105/p50 NF-κB subunit encoded by the NFKB1 gene in these cell lines. An initial NF-κB activation event enhances the recruitment of p65 and ELF1 to the NFKB1 promoter, leading to p65- and ELF1-dependent synthesis of p105/p50, which promotes an exchange of NF-κB complexes to p50-containing complexes with an increased DNA-binding activity to certain NF-κB target elements. Subsequent stimulation of these cells with an anticancer agent, etoposide, results in augmented NF-κB-dependent p21waf1/ciP1 induction and increased chemoresistance of the leukemia cells. Thus, we propose that low basal NFKB1 expression coupled with sequential NF-κB activation events can promote increased chemoresistance in certain T leukemic cells. Copyright © 2006 American Association for Cancer Research.