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Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS

Marta Barradas1, Emma Anderton, Juan Carlos Acosta

  • 1Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, United Kingdom.

Genes & Development
|May 20, 2009
PubMed

Insights

Oncogenic RAS signaling activates JMJD3, a demethylase that overrides Polycomb repression of the INK4a/ARF locus. This leads to cellular senescence, suggesting JMJD3’s role as a tumor suppressor.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Epigenetics

Background:

  • The INK4a/ARF tumor suppressor locus is crucial for cellular senescence.
  • Polycomb group (PcG) proteins repress INK4a/ARF transcription.
  • Oncogenic RAS signaling pathways influence tumor suppressor gene expression.

Purpose of the Study:

  • To investigate how oncogenic RAS signaling affects PcG-mediated repression of the INK4a/ARF locus.
  • To elucidate the role of JMJD3 and EZH2 in this process.
  • To determine the functional consequences of JMJD3 activation on cellular senescence.

Main Methods:

  • Analysis of INK4a/ARF locus regulation in human and mouse fibroblasts.
  • Investigation of JMJD3 and EZH2 expression and activity.
  • Assessment of cellular senescence markers and cell cycle arrest.

Main Results:

  • Oncogenic RAS signaling activates JMJD3 and down-regulates EZH2, overriding PcG repression of INK4a.
  • JMJD3 activation leads to p16(INK4a)-dependent arrest in human fibroblasts.
  • JMJD3 activation causes p53-dependent arrest in mouse embryo fibroblasts, mimicking RAS effects.

Conclusions:

  • JMJD3 is directly implicated in regulating the INK4a/ARF locus during oncogene-induced senescence.
  • JMJD3 activation by oncogenic RAS contributes to cellular senescence.
  • JMJD3 exhibits tumor suppressor capabilities by inducing senescence.

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