Proto-oncoprotein ZBTB2 represses transcription activation of RELA gene by Sp1 (178.6)

Abstract

Abstract Recently, we found that ZBTB2, a POK family transcription factor, is a proto-oncogenic control gene of the p53 pathway and is a transcription repressor of the p21 by inhibiting p53 and Sp1. NF-κB is a protein complex that controls the transcription. NF-kB 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-kB has been linked to cancer, inflammatory diseases, viral infection, and improper development. Surprisingly little is known how transcription of the genes encoding p65or p50 is regulated. Interestingly, we found that ZBTB2 represses transcription activation of pNF-kB-Luc reporter by NF-kB, and knock-down of ZBTB2 expression derepresses transcription. Our data suggested that ZBTB2 represses transcription of NF-kB responsive gene by repressing expression of the genes encoding NF-kB subunit p65. Sp1 plays a key role in the expression of RELA gene and ZBTB2 repressed transcription of the gene by acting on the three proximal Sp1 binding elements. Co-IP/western blot and GST fusion protein pull-down assays revealed direct protein-protein interaction between Sp1 and ZBTB2. EMSA, ChIP, and oligonucleotide pull-down assays revealed that ZBTB2 represses transcription of RELA gene by inhibiting Sp1 binding by protein-protein interaction. Functional significances and the details of regulatory mechanism are under investigation..