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

K. M. Lee, W. I. Choi, D. I. Koh, Y. J. Kim, B. N. Jeon, J. H. Yoon, C. E. Lee, S. H. Kim, J. Oh, M. W. Hur

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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-box3 (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.

Original languageEnglish
Pages (from-to)1442-1458
Number of pages17
JournalOncogene
Volume31
Issue number11
DOIs
Publication statusPublished - 2012 Mar 15

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Lee, K. M., Choi, W. I., Koh, D. I., Kim, Y. J., Jeon, B. N., Yoon, J. H., Lee, C. E., Kim, S. H., Oh, J., & Hur, M. W. (2012). The proto-oncoprotein KR-POK represses transcriptional activation of CDKN1A by MIZ-1 through competitive binding. Oncogene, 31(11), 1442-1458. https://doi.org/10.1038/onc.2011.331