ZBTB2 represses transcription activation of RelA/p65 gene by Sp1

Abstract

Recently, we found that ZBTB2, a POK family transcription factor, is a proto-oncoprotein controlling the genes of the p53 pathway. ZBTB2 represses transcription of p21WAF/CDKN1A by inhibiting p53 and Sp1. NF-κB (nuclear factor-κB) is a protein complex that controls the transcription. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, and ultraviolet irradiation. Incorrect regulation of NF-κB has been linked to cancer, inflammatory diseases, viral infection, and improper development. Surprisingly, little is known about how transcription of the genes encoding RelA/p65 or NF-κB1/p50 is regulated. Our data suggested that ZBTB2 can repress transcription of NF-κB responsive genes by repressing expression of RelA/p65 gene encoding NF-κB subunit p65. Sp1 plays a key role in the expression of RelA/p65 and ZBTB2 represses transcription of the gene by acting on the proximal Sp1 binding elements. Co-immunoprecipitation/western blot and GST fusion protein pull-down assays revealed that ZBTB2 and Sp1 interact directly. EMSA, ChIP, and oligonucleotide pull-down assays revealed that ZBTB2 represses transcription of RelA/p65 by inhibiting Sp1 binding by protein-protein interaction and ZBTB2 binding of the proximal Sp1 binding elements. Moreover, potent transcriptional activation of pNF-B-Luc by TNFα was repressed by ZBTB2. Overall, ZBTB2 may inhibit the NF-B signaling by repressing the expression of RelA/p65 gene. ZBTB2 may play important roles in NF-kB-mediated cellular processes such as apoptosis, cell adhesion, proliferation, the innate and adaptive immunity, inflammation, and tissue remodeling.