Abstract
We found that ZBTB2, a POK family transcription factor, is a potent repressor of the ARF-HDM2-p53-p21 pathway important in cell cycle regulation. ZBTB2 repressed transcription of the ARF, p53, and p21 genes, but activated the HDM2 gene. In particular, ZBTB2 repressed transcription of the p21 gene by acting on the two distal p53 binding elements and the proximal Sp1 binding GC-box 5/6 elements. ZBTB2 directly interacted with Sp1 via its POZ domain and zinc fingers, which was important in the repression of transcription activation by Sp1. ZBTB2 and Sp1 competed with each other in binding to the GC-box 5/6 elements and the two p53 binding elements. ZBTB2 directly interacted with p53 via its zinc fingers, inhibiting p53 binding and repressing transcription activation by p53. The POZ domain, required for transcription repression, interacted with corepressors such as BCoR, NCoR, and SMRT. The interactions deacetylated histones Ac-H3 and -H4 at the proximal promoter. Although ectopic ZBTB2 stimulated cell proliferation, knock-down of ZBTB2 expression decreased cell proliferation and DNA synthesis. Overall, our data suggest that ZBTB2 is a potential proto-oncogenic master control gene of the p53 pathway and, in particular, is a potent transcription repressor of the cell cycle arrest gene p21 by inhibiting p53 and Sp1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-Ribosylation Factor 1 / genetics
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ADP-Ribosylation Factor 1 / metabolism
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Acetylation
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Animals
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Binding, Competitive / physiology
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Cell Division / physiology
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Drosophila
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HeLa Cells
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Histones / genetics
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Histones / metabolism
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Humans
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Kidney / cytology
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Mice
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Mice, Inbred Strains
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Promoter Regions, Genetic / physiology
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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RNA, Messenger / metabolism
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Repressor Proteins / chemistry
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism*
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S Phase / physiology
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Sp1 Transcription Factor / metabolism
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / physiology
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism*
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Two-Hybrid System Techniques
Substances
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Histones
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RNA, Messenger
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Repressor Proteins
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Sp1 Transcription Factor
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Transcription Factors
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Tumor Suppressor Protein p53
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ZBTB2 protein, human
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ZBTB2 protein, mouse
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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ADP-Ribosylation Factor 1