KR-POK Interacts with p53 and Represses Its Ability to Activate Transcription of p21WAF1/CDKN1A

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-03, Vol.72 (5), p.1137-1148
• Main Authors: JEON, Bu-Nam, KIM, Min-Kyeong, LEE, Kyung-Ryul, NEPHEW, Kenneth P, HUR, Man-Wook, CHOI, Won-Ii, KOH, Dong-In, HONG, Sung-Yi, KIM, Kyung-Sup, KIM, Minjung, YUN, Chae-Ok, JUYONG YOON, CHOI, Kang-Yell
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Female; Fibroblasts - metabolism; Gene Knockout Techniques; Genes, p53; Humans; Kidney Neoplasms - genetics; Medical sciences; Mice; Mice, Nude; NIH 3T3 Cells; Pharmacology. Drug treatments; Promoter Regions, Genetic; Proteins - genetics; Proto-Oncogene Proteins; Transcription Factors - metabolism; Transcriptional Activation; Tumors; Zinc Fingers
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-2433

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.