p53- and Mdm2-independent repression of NF-kappa B transactivation by the ARF tumor suppressor

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Published on: August 4, 2019

Sonia Rocha1, Kirsteen J Campbell, Neil D Perkins

  • 1School of Life Sciences, Division of Gene Regulation and Expression, MSI/WTB Complex, Dow Street, University of Dundee, Dundee, DD1 5EH, Scotland, United Kingdom.

Molecular Cell
|July 31, 2003
PubMed

Insights

The tumor suppressor ARF inhibits the transcription factor NF-kappa B, independent of p53. This finding reveals ARF

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Oncogenes can drive cancer by activating transcription factors like NF-kappa B, which can antagonize tumor suppressors such as p53.
  • The tumor suppressor ARF is known to activate p53 by inhibiting Mdm2, playing a crucial role in cellular defense against oncogenic transformation.

Purpose of the Study:

  • To investigate the role of ARF in regulating NF-kappa B activity, independent of its known p53-activating pathway.
  • To elucidate the molecular mechanism by which ARF might control NF-kappa B function.

Main Methods:

  • Assays to measure NF-kappa B transcriptional activity and antiapoptotic function.
  • Co-immunoprecipitation to assess protein-protein interactions between ARF, RelA, and HDAC1.
  • Studies involving cells with varying ARF expression levels, including responses to oncogene Bcr-Abl.

Main Results:

  • ARF directly inhibits NF-kappa B transcriptional activity and its pro-survival function independently of Mdm2 and p53.
  • ARF represses the RelA transcriptional activation domain by promoting its association with histone deacetylase HDAC1.
  • The cellular response to the oncogene Bcr-Abl is modulated by the ARF status of the cell, impacting NF-kappa B signaling.

Conclusions:

  • ARF possesses a novel function in directly suppressing NF-kappa B signaling, thereby providing an additional layer of tumor suppression.
  • This ARF-mediated inhibition of NF-kappa B, involving HDAC1, offers a new perspective on how cells counteract oncogene-induced transformation.

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