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Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1

Abstract

The tumor suppressor gene hypermethylated in cancer 1 (HIC1), located on human chromosome 17p13.3, is frequently silenced in cancer by epigenetic mechanisms. Hypermethylated in cancer 1 belongs to the bric à brac/poxviruses and zinc-finger family of transcription factors and acts by repressing target gene expression. It has been shown that enforced p53 expression leads to increased HIC1 mRNA, and recent data suggest that p53 and Hic1 cooperate in tumorigenesis. In order to elucidate the regulation of HIC1 expression, we have analysed the HIC1 promoter region for p53-dependent induction of gene expression. Using progressively truncated luciferase reporter gene constructs, we have identified a p53-responsive element (PRE) 500 bp upstream of the TATA-box containing promoter P0 of HIC1, which is sequence specifically bound by p53 in vitro as assessed by electrophoretic mobility shift assays. We demonstrate that this HIC1 p53-responsive element (HIC1.PRE) is necessary and sufficient to mediate induction of transcription by p53. This result is supported by the observation that abolishing endogenous wild-type p53 function prevents HIC1 mRNA induction in response to UV-induced DNA damage. Other members of the p53 family, notably TAp73β and ΔNp63α, can also act through this HIC1.PRE to induce transcription of HIC1, and finally, hypermethylation of the HIC1 promoter attenuates inducibility by p53.

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Acknowledgements

We thank Dr D Leprince (Institut Pasteur de Lille, Lille, France) and Dr R Iggo (Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland) for helpful discussions; Dr B Vogelstein (The Sidney Kimmel Comprehensive Cancer Center and The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MA) for providing HCT116 p53−/−; and Dr R Agami (The Netherlands Cancer Institute, Amsterdam, The Netherlands), Dr G Melino (MRC, Toxicology Unit, Leicester, UK) and Dr P Sun (The Scripps Research Institute, La Jolla, CA) for providing plasmid constructs. This work was supported by Grants SNF 3100-067213, the Bernese Cancer League, the Werner and Hedy Berger-Janser Stiftung for Cancer Research to MFF and AT, Grant NIH AI49165 to BET and Grant OCS 01510-02-2004 of the Swiss Cancer League to ACA. MPT is recipient of a Swiss Federation against Cancer fellowship (No. BIL OCS-01198-09-2001).

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Correspondence to M F Fey.

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Britschgi, C., Rizzi, M., Grob, T. et al. Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1. Oncogene 25, 2030–2039 (2006). https://doi.org/10.1038/sj.onc.1209240

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Keywords

  • HIC1
  • p53
  • transcriptional target
  • HIC1.PRE
  • p73

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