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Transcription factor NFAT1 activates the mdm2 oncogene independent of p53

Xu Zhang1, Zhuo Zhang, Jianwen Cheng

  • 1Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.

The Journal of Biological Chemistry
|July 13, 2012
PubMed

Insights

Nuclear Factor of Activated T-cells 1 (NFAT1) directly up-regulates MDM2 expression by binding to its promoter. This elevates MDM2 levels, suppressing tumor suppressor p53, and is observed in hepatocellular carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • MDM2 overexpression in cancers with non-functional p53 suggests p53-independent regulation.
  • Nuclear Factor of Activated T-cells (NFAT) signaling dysregulation is linked to cancer development and progression.

Purpose of the Study:

  • To investigate the role of NFAT1 in regulating MDM2 expression.
  • To explore the functional consequences of NFAT1-mediated MDM2 up-regulation on p53.
  • To examine the expression of NFAT1 and MDM2 in hepatocellular carcinoma.

Main Methods:

  • Analysis of the human mdm2 P2 promoter for NFAT1 binding sites.
  • In vitro and in vivo binding assays to confirm NFAT1-mdm2 promoter interaction.
  • Assessment of MDM2 and p53 levels following enforced NFAT1 expression.
  • Comparison of NFAT1 and MDM2 expression in hepatocellular carcinoma and normal liver tissues.

Main Results:

  • A consensus NFAT1 binding site was identified in the human mdm2 P2 promoter.
  • NFAT1 directly binds to the mdm2 P2 promoter, increasing mdm2 transcription.
  • Enforced NFAT1 expression leads to higher MDM2 protein levels and reduced p53 activity.
  • Both NFAT1 and MDM2 are overexpressed in hepatocellular carcinoma, with a positive correlation between their levels.

Conclusions:

  • NFAT1 directly controls MDM2 transcription through its P2 promoter.
  • NFAT1-mediated MDM2 up-regulation inhibits p53 function, potentially promoting cancer.
  • NFAT1 is a novel regulator of MDM2 and a potential target in cancer therapy.

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