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KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A.

Authors
 Bu-Nam Jeon  ;  Min-Kyeong Kim  ;  Won-Il Choi  ;  Dong-In Koh  ;  Sung-Yi Hong  ;  Kyung-Sup Kim  ;  Minjung Kim  ;  Chae-Ok Yun  ;  Juyong Yoon  ;  Kang-Yell Choi  ;  Kyung-Ryul Lee  ;  Kenneth P. Nephew  ;  Man-Wook Hur 
Citation
 CANCER RESEARCH, Vol.72(5) : 1137-1148, 2012 
Journal Title
 CANCER RESEARCH 
ISSN
 0008-5472 
Issue Date
2012
MeSH
Animals ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21/genetics* ; Female ; Fibroblasts/metabolism ; Gene Knockout Techniques ; Genes, p53* ; Humans ; Kidney Neoplasms/genetics* ; Mice ; Mice, Nude ; NIH 3T3 Cells ; Promoter Regions, Genetic ; Proteins/genetics* ; Proto-Oncogene Proteins ; Transcription Factors/metabolism ; Transcriptional Activation* ; Zinc Fingers
Keywords
Animals ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21/genetics* ; Female ; Fibroblasts/metabolism ; Gene Knockout Techniques ; Genes, p53* ; Humans ; Kidney Neoplasms/genetics* ; Mice ; Mice, Nude ; NIH 3T3 Cells ; Promoter Regions, Genetic ; Proteins/genetics* ; Proto-Oncogene Proteins ; Transcription Factors/metabolism ; Transcriptional Activation* ; Zinc Fingers
Abstract
Transcriptional regulation by p53 is thought to play a role in its ability to suppress tumorigenesis. However, there remain gaps in understanding about how p53 regulates transcription and how disrupting this function may promote cancer. Here we report a role in these processes for the kidney cancer-related gene KR-POK (ZBTB7C), a POZ domain and Krüppel-like zinc finger transcription factor that we found to physically interact with p53. Murine embryonic fibroblasts isolated from genetically deficient mice (Kr-pok(-/-) MEFs) exhibited a proliferative defect relative to wild-type mouse embryonic fibroblasts (MEF). The zinc finger domain of Kr-pok interacted directly with the DNA binding and oligomerization domains of p53. This interaction was essential for Kr-pok to bind the distal promoter region of the CDKN1A gene, an important p53 target gene encoding the cell-cycle regulator p21WAF1, and to inhibit p53-mediated transcriptional activation of CDKN1A. Kr-pok also interacted with the transcriptional corepressors NCoR and BCoR, acting to repress histone H3 and H4 deacetylation at the proximal promoter region of the CDKN1A gene. Importantly, Kr-pok(-/-) MEFs displayed an enhancement in CDKN1A transactivation by p53 during the DNA damage response, without any parallel changes in transcription of either the p53 or Kr-pok genes themselves. Furthermore, Kr-pok promoted cell proliferation in vitro and in vivo, and its expression was increased in more than 50% of the malignant human kidney cancer cases analyzed. Together, our findings define KR-POK as a transcriptional repressor with a pro-oncogenic role that relies upon binding to p53 and inhibition of its transactivation function.
Files in This Item:
T201200680.pdf Download
DOI
22253232
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Koh, Dong In(고동인)
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Kim, Min Kyeong(김민경)
Yun, Chae Ok(윤채옥)
Jeon, Bu Nam(전부남)
Choi, Won Il(최원일)
Hur, Man Wook(허만욱) ORCID logo https://orcid.org/0000-0002-3416-1334
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/89871
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