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Ras induces mediator complex exchange on C/EBP beta

Xianming Mo1, Elisabeth Kowenz-Leutz, Hong Xu

  • 1Max-Delbrück-Center for Molecular Medicine, Robert-Roessle-Str. 10, 13092 Berlin, Germany.

Molecular Cell
|February 5, 2004
PubMed

Insights

CCAAT-enhancer-binding protein beta (C/EBPbeta) functions as a repressor but becomes an activator via Ras oncoprotein signaling. This Ras-induced change dictates selective interactions with Mediator complexes for gene regulation.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Gene Regulation

Background:

  • CCAAT-enhancer-binding protein beta (C/EBPbeta) is a transcription factor that intrinsically represses gene expression.
  • C/EBPbeta regulates critical cellular processes including differentiation, proliferation, apoptosis, and tumorigenesis.
  • The Ras oncoprotein activates C/EBPbeta by phosphorylating a MAPK site, converting it from a repressor to an activator.

Purpose of the Study:

  • To investigate the mechanism by which C/EBPbeta activation by oncogenic Ras leads to differential gene activation.
  • To elucidate the role of Mediator complexes in C/EBPbeta-mediated transcriptional regulation.
  • To determine how structural alterations in C/EBPbeta influence its interaction with Mediator complexes.

Main Methods:

  • Utilized knockdown experiments to assess the role of the CRSP130/Sur2 subunit.
  • Investigated the interaction between C/EBPbeta and Mediator complexes under conditions of oncogenic Ras signaling or C/EBPbeta mutations.
  • Analyzed the association of Mediator complexes with RNA polymerase II.

Main Results:

  • C/EBPbeta activation involves a conformational change.
  • Both active and repressive forms of C/EBPbeta interact with Mediator complexes via the CRSP130/Sur2 subunit.
  • CRSP130/Sur2 is a component of two distinct Mediator complexes: one transcriptionally active (containing CRSP70) and one inactive (containing CDK8).
  • Knockdown of CRSP130/Sur2 inhibits C/EBPbeta-mediated transactivation.
  • Oncogenic Ras signaling or activating C/EBPbeta mutations promote the selection of the transcriptionally active Mediator complex, which also binds RNA polymerase II.

Conclusions:

  • Ras-induced structural changes in C/EBPbeta are crucial for its function.
  • C/EBPbeta selects specific Mediator complexes based on its activation state.
  • Differential interaction with Mediator complexes determines the specific gene activation patterns regulated by C/EBPbeta.

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