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 P Nephew, Man-Wook Hur

Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Severance Institute of Biomedical Science, Seoul, Korea.

Cancer research 2012 Mar 1

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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.

Citation

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. KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A. Cancer research. 2012 Mar 1;72(5):1137-48