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Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation
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Identification of a co-activator that links growth factor signalling to c-Jun/AP-1 activation

Clare C Davies1, Atanu Chakraborty, Filippo Cipriani

  • 1Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3PX, UK.

Nature Cell Biology
|September 21, 2010
PubMed

Insights

Researchers discovered RACO-1, a protein linking growth factors to c-Jun activation, crucial for cell proliferation. RACO-1 stabilization by MEK/ERK signaling promotes AP-1 activity and cell growth.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • The AP-1 transcription factor c-Jun is vital for cellular proliferation.
  • The molecular mechanisms connecting growth factors to c-Jun activation remain unclear.

Purpose of the Study:

  • To identify and characterize novel co-activators of c-Jun involved in growth factor signaling.
  • To elucidate the role of RACO-1 in AP-1 mediated cellular proliferation and cancer development.

Main Methods:

  • Protein interaction studies to identify RACO-1 and c-Jun binding.
  • Analysis of RACO-1 ubiquitylation and stabilization via MEK/ERK pathway.
  • Gene silencing and overexpression studies in cellular and animal models.
  • Assessment of AP-1 target gene expression and cellular proliferation rates.

Main Results:

  • A new protein, RACO-1 (RING domain AP-1 co-activator-1), was identified as a c-Jun co-activator.
  • Growth factor signaling stabilizes RACO-1 through MEK/ERK-dependent Lys 63-linked ubiquitylation, preventing degradation.
  • RACO-1 depletion inhibits proliferation and AP-1 target gene expression; its overexpression promotes tumor formation.

Conclusions:

  • RACO-1 acts as a critical link between growth factor signaling and c-Jun/AP-1 activation.
  • RACO-1 is essential for AP-1 function in cell proliferation and contributes to aberrant proliferation in cancer models.

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