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

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 Nephew, Man Wook Hur

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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.

Original languageEnglish
Pages (from-to)1137-1148
Number of pages12
JournalCancer Research
Volume72
Issue number5
DOIs
StatePublished - Mar 1 2012

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Transcriptional Activation
Kidney Neoplasms
Zinc Fingers
Genetic Promoter Regions
Histones
Fibroblasts
Genes
Co-Repressor Proteins
Neoplasm Genes
p53 Genes
DNA Damage
Cell Cycle
Carcinogenesis
Transcription Factors
Cell Proliferation
DNA
Neoplasms
In Vitro Techniques
BTB-POZ Domain

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jeon, B. N., Kim, M. K., Choi, W. I., Koh, D. I., Hong, S. Y., Kim, K. S., ... Hur, M. W. (2012). KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A. Cancer Research, 72(5), 1137-1148. https://doi.org/10.1158/0008-5472.CAN-11-2433

KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A. / Jeon, Bu Nam; Kim, Min Kyeong; Choi, Won Il; Koh, Dong In; Hong, Sung Yi; Kim, Kyung Sup; Kim, Minjung; Yun, Chae Ok; Yoon, Juyong; Choi, Kang Yell; Lee, Kyung Ryul; Nephew, Kenneth; Hur, Man Wook.

In: Cancer Research, Vol. 72, No. 5, 01.03.2012, p. 1137-1148.

Research output: Contribution to journalArticle

Jeon, BN, Kim, MK, Choi, WI, Koh, DI, Hong, SY, Kim, KS, Kim, M, Yun, CO, Yoon, J, Choi, KY, Lee, KR, Nephew, K & Hur, MW 2012, 'KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A', Cancer Research, vol. 72, no. 5, pp. 1137-1148. https://doi.org/10.1158/0008-5472.CAN-11-2433
Jeon, Bu Nam ; Kim, Min Kyeong ; Choi, Won Il ; Koh, Dong In ; Hong, Sung Yi ; Kim, Kyung Sup ; Kim, Minjung ; Yun, Chae Ok ; Yoon, Juyong ; Choi, Kang Yell ; Lee, Kyung Ryul ; Nephew, Kenneth ; Hur, Man Wook. / KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A. In: Cancer Research. 2012 ; Vol. 72, No. 5. pp. 1137-1148.
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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 Kr{\"u}ppel-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.",
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