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Cell Cycle, Cell Death, and Senescence

Nuclear Factor-B Dimer Exchange Promotes a p21^waf1/cip1 Superinduction Response in Human T Leukemic Cells

Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin

Requests for reprints: Shigeki Miyamoto, Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin-Madison, 301 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706. Phone: 608-262-9281; Fax: 608-262-1257. E-mail: smiyamot{at}wisc.edu

The nuclear factor-B (NF-B)/Rel transcription factors are recognized as critical apoptosis regulators. We reported previously that NF-B contributes to chemoresistance of CEM human T leukemic cells in part through its ability to induce p21^waf1/cip1. Here, we provide evidence that sequential NF-B-activating signals induce heightened NF-B DNA binding and p21^waf1/cip1 induction in CEM and additional T leukemic cell lines. This response arises from exceedingly low basal expression of the p105/p50 NF-B subunit encoded by the NFKB1 gene in these cell lines. An initial NF-B 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-B complexes to p50-containing complexes with an increased DNA-binding activity to certain NF-B target elements. Subsequent stimulation of these cells with an anticancer agent, etoposide, results in augmented NF-B-dependent p21^waf1/cip1 induction and increased chemoresistance of the leukemia cells. Thus, we propose that low basal NFKB1 expression coupled with sequential NF-B activation events can promote increased chemoresistance in certain T leukemic cells. (Mol Cancer Res 2006;4(2):101–12)

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