ZBTB2, a novel master regulator of the p53 pathway.
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.
Jeon
Bu-Nam
BN
Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Seoul 120-752, Korea.
Choi
Won-Il
WI
Yu
Mi-Young
MY
Yoon
A-Rum
AR
Kim
Myung-Hwa
MH
Yun
Chae-Ok
CO
Hur
Man-Wook
MW
D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004330:Drosophila; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006657:Histones; D012333:RNA, Messenger; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C544396:ZBTB2 protein, human; C544397:ZBTB2 protein, mouse; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020823:ADP-Ribosylation Factor 1