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The proto-oncoprotein KR-POK represses transcriptional activation of CDKN1A by MIZ-1 through competitive binding

Authors
 K M Lee ; W I Choi ; M W Hur ; J Oh ; S H Kim ; C E Lee ; J H Yoon ; B N Jeon ; Y J Kim ; D I Koh 
Citation
 Oncogene, Vol.31(11) : 1442~1458, 2012 
Journal Title
 Oncogene 
ISSN
 0950-9232 
Issue Date
2012
Abstract
The BTB/POZ family of proteins has been implicated in multiple biological processes, including tumourigenesis, DNA damage responses and cell cycle progression and development. MIZ-1 (Myc-interacting zinc-finger protein 1) is known to activate transcription of CDKN1A. We recently found that a kidney cancer-related POK transcription factor, KR-POK, is highly expressed in kidney, brain and bone marrow cancer tissues and is a potential proto-oncoprotein. Mouse Kr-pok represses transcription of the CDKN1A by acting on the proximal promoter. The BiFC/FRET assay, co-immunoprecipitation and glutathione S-transferase-fusion protein pull-down assay indicate that MIZ-1 and Kr-pok interact via their POZ domains. Oligoucleotide pull-down assays and chromatin immunoprecipitation assays revealed that MIZ-1 binds to the proximal GC-box#3 (bp, -55 to -63) and the MIZ-1-binding elements, MRE-A (bp, -90 to -64) and MRE-B (bp, -27 to -17). Interestingly, MIZ-1 also binds to the distal p53-binding elements. Kr-pok binds to the proximal GC-box#1 (bp, -95 to -100) and #3 (bp, -55 to -63) relatively strongly. It also shows weak binding to the MREs and the distal p53-binding elements. Kr-pok competes with MIZ-1 in binding to these elements and represses transcription by inhibiting MIZ-1/p300 recruitment, which decreases the acetylation of histones H3 and H4. Our data indicate that Kr-pok stimulates cell proliferation by interfering with the function of MIZ-1 in CDKN1A gene transcription using a mechanism that is radically different from other MIZ-1-interacting proteins, such as B-cell lymphoma 6, c-Myc and Gfi-1.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/91581
DOI
10.1038/onc.2011.331
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Biochemistry & Molecular Biology
Yonsei Authors
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Link
 http://www.nature.com/onc/journal/v31/n11/full/onc2011331a.html
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