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Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment

Charles E Foulds1, Mary L Nelson, Adam G Blaszczak

  • 1Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112-5550, USA.

Molecular and Cellular Biology
|December 2, 2004
PubMed

Insights

Mitogen-activated protein kinase (MAPK) phosphorylation enhances transcription factor Ets-1/Ets-2 activity by improving coactivator recruitment. This mechanism links Ras/MAPK signaling to Ets proteins, impacting development and cancer.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Regulation

Background:

  • Cell signaling pathways modulate gene expression through transcription factor regulation.
  • Mitogen-activated protein kinases (MAPKs) are key regulators of cellular responses.
  • Ets transcription factors (Ets-1, Ets-2) play critical roles in development and tumorigenesis.

Purpose of the Study:

  • To investigate the mechanism by which MAPK signaling enhances Ets transcription factor activity.
  • To identify specific coactivators involved in this process.
  • To elucidate the functional significance of MAPK-mediated Ets protein modifications.

Main Methods:

  • Affinity chromatography using phosphorylated Ets proteins to screen nuclear extracts.
  • Purified protein binding assays to confirm direct interactions.
  • In vitro and in vivo assays to assess transcriptional activity and protein interactions.

Main Results:

  • MAPK phosphorylation of Ets-1 and Ets-2 enhances their transactivation potential.
  • Phosphorylation promotes preferential recruitment of coactivators CREB binding protein (CBP) and p300.
  • A specific phosphorylation site N-terminal to the Pointed (PNT) domain and the PNT domain itself are crucial for this interaction.
  • MAPK-enhanced Ets-2 activity is potentiated by CBP coexpression.
  • Phosphorylation-dependent interaction between CBP and Ets-2 was observed in vivo.

Conclusions:

  • MAPK phosphorylation creates a distinct interface for transcription factor-coactivator complex formation.
  • Inducible CBP/p300 binding is functionally significant for MAPK-mediated gene regulation.
  • This study reveals a mechanistic link between Ras/MAPK signaling and Ets transcription factors relevant to development and cancer.

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