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

Bu-Nam Jeon1, Min-Kyeong Kim, Won-Il Choi

  • 1Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Severance Institute of Biomedical Science, Seoul, Korea.

Cancer Research
|January 19, 2012
PubMed

Insights

The kidney cancer gene KR-POK interacts with p53 to inhibit its tumor-suppressing activity. Loss of KR-POK enhances p53

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Transcriptional Regulation

Background:

  • The tumor suppressor protein p53 regulates gene transcription, but its precise mechanisms and links to cancer are not fully understood.
  • Understanding how p53's transcriptional function is disrupted in cancer is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of the kidney cancer-related gene KR-POK (ZBTB7C) in p53-mediated transcriptional regulation.
  • To elucidate the molecular mechanisms by which KR-POK influences p53 activity and its potential role in tumorigenesis.

Main Methods:

  • Co-immunoprecipitation to detect physical interaction between KR-POK and p53.
  • Analysis of murine embryonic fibroblasts (MEFs) from Kr-pok deficient mice.
  • Chromatin immunoprecipitation (ChIP) assays to assess gene promoter binding.
  • Reporter assays to measure transcriptional activation of CDKN1A.
  • Histone deacetylase activity assays.
  • In vitro and in vivo proliferation assays.
  • Analysis of KR-POK expression in human kidney cancer samples.

Main Results:

  • KR-POK physically interacts with p53, specifically with its DNA binding and oligomerization domains.
  • KR-POK binds to the CDKN1A promoter and inhibits p53-mediated transactivation of this gene.
  • KR-POK recruits corepressors NCoR and BCoR to repress histone deacetylation at the CDKN1A promoter.
  • Kr-pok(-/-) MEFs show enhanced CDKN1A transactivation by p53 upon DNA damage.
  • KR-POK promotes cell proliferation in vitro and in vivo.
  • Increased KR-POK expression is observed in over 50% of analyzed human kidney cancers.

Conclusions:

  • KR-POK functions as a transcriptional repressor that inhibits p53's tumor-suppressive transcriptional activity.
  • The interaction between KR-POK and p53 is critical for KR-POK's repressive function on CDKN1A.
  • KR-POK possesses a pro-oncogenic role in kidney cancer by suppressing p53-mediated tumor suppression.

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