Nuclear factor-kappaB dimer exchange promotes a p21(waf1/cip1) superinduction response in human T leukemic cells.
The nuclear factor-kappaB (NF-kappaB)/Rel transcription factors are recognized as critical apoptosis regulators. We reported previously that NF-kappaB 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-kappaB-activating signals induce heightened NF-kappaB 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-kappaB subunit encoded by the NFKB1 gene in these cell lines. An initial NF-kappaB 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-kappaB complexes to p50-containing complexes with an increased DNA-binding activity to certain NF-kappaB target elements. Subsequent stimulation of these cells with an anticancer agent, etoposide, results in augmented NF-kappaB-dependent p21(waf1/cip1) induction and increased chemoresistance of the leukemia cells. Thus, we propose that low basal NFKB1 expression coupled with sequential NF-kappaB activation events can promote increased chemoresistance in certain T leukemic cells.
Chang
Pei-Yun
PY
Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin-Madison, 301 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706, USA.
Miyamoto
Shigeki
S
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D005047:Etoposide / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047468:Immunoprecipitation; D015458:Leukemia, T-Cell / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D014157:Transcription Factors; D005047:Etoposide; D004247:DNA