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The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF

Ulrike Philippar1, Gerhard Schratt, Christoph Dieterich

  • 1Abt. Molekularbiologie, Institut für Zellbiologie, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany.

Molecular Cell
|December 22, 2004
PubMed

Insights

RhoA signaling controls muscle differentiation via the serum response factor (SRF). This study reveals FHL2 protein selectively regulates SRF target genes, providing a novel autoregulatory mechanism for muscle-specific gene expression.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Gene Regulation

Background:

  • RhoA signaling is crucial for muscle differentiation by modulating serum response factor (SRF) activity.
  • The precise integration of RhoA signaling at SRF target promoters for muscle-lineage-specific expression remains unclear.

Purpose of the Study:

  • To investigate how RhoA signaling is integrated at SRF target promoters.
  • To identify SRF target genes involved in muscle differentiation and understand their regulation by RhoA.
  • To elucidate the role of the transcriptional cofactor FHL2 in this process.

Main Methods:

  • Large-scale expression profiling
  • Bioinformatic analysis
  • Biochemical approaches (e.g., protein interaction studies, promoter binding assays)

Main Results:

  • Identified Fhl2 as an SRF target gene regulated by RhoA activation.
  • Demonstrated physical interaction between FHL2 protein and SRF.
  • Showed FHL2 binds promoters of SRF-responsive smooth muscle (SM) genes, but not immediate-early genes (IEGs), upon RhoA activation.
  • Revealed FHL2 antagonizes SM gene induction by competing with MAL/MRTF-A for SRF binding.

Conclusions:

  • Identified an autoregulatory mechanism where FHL2 selectively regulates a subset of RhoA-activated SRF target genes.
  • FHL2 plays a critical role in distinguishing between different classes of SRF target genes in response to RhoA signaling.
  • This mechanism contributes to muscle-lineage-specific gene expression patterns.

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