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

Oncogene volume 31, pages 1442–1458 (2012)Cite this article

A Corrigendum to this article was published on 12 June 2017

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.

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Acknowledgements

This work was mainly funded by a Basic Science Research Grant (314-2008-1-E00030 to M-W Hur and C-E Lee), and MRC (R13-2002-054-05002-0) from the National Research Foundation of Korea, and also by a Faculty Research Grant from Yonsei University School of Medicine.

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  1. Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, SeoDaeMoon-Ku, Seoul, Korea

    K M Lee, W I Choi, D I Koh, Y J Kim, B N Jeon, J H Yoon & M W Hur

  2. Department of Biological Science, Sungkyunkwan University, Suwon, Korea

    C E Lee, S H Kim & J Oh

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Lee, K., Choi, W., Koh, D. et al. The proto-oncoprotein KR-POK represses transcriptional activation of CDKN1A by MIZ-1 through competitive binding. Oncogene 31, 1442–1458 (2012). https://doi.org/10.1038/onc.2011.331

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