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Repression of PDGF-R-α after cellular injury involves TNF-α, formation of a c-Fos-YY1 complex, and negative

Ning Zhang1, Cecilia W S Chan, Estella Sanchez-Guerrero

  • 1Centre for Vascular Research, University of New South Wales, Sydney, Australia.

American Journal of Physiology. Cell Physiology
|February 11, 2012
PubMed

Insights

Tumor necrosis factor-alpha (TNF-α) released after fibroblast injury suppresses platelet-derived growth factor receptor-alpha (PDGF-R-α) expression. This involves c-Fos, Yin Yang 1 (YY1), and histone deacetylase (HDAC) activity, revealing a key transcriptional regulation mechanism in wound healing.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Wound healing involves complex cellular interactions and gene regulation.
  • Transcriptional control mechanisms governing fibroblast gene expression post-injury are not fully understood.
  • Platelet-derived growth factor receptor-alpha (PDGF-R-α) plays a crucial role in fibroblast function during healing.

Purpose of the Study:

  • To elucidate the transcriptional mechanisms underlying PDGF-R-α downregulation in fibroblasts following injury.
  • To investigate the role of tumor necrosis factor-alpha (TNF-α) in regulating PDGF-R-α expression.
  • To identify the specific molecular players involved in TNF-α-mediated repression of PDGF-R-α.

Main Methods:

  • Utilized small interfering RNA (siRNA) to target c-Fos and Yin Yang 1 (YY1).
  • Performed co-immunoprecipitation to study protein complex formation.
  • Conducted chromatin immunoprecipitation (ChIP) assays to analyze promoter enrichment.
  • Employed suberoylanilide hydroxamic acid (SAHA) and HDAC-1 siRNA to assess histone deacetylase (HDAC) activity.

Main Results:

  • TNF-α significantly decreases PDGF-R-α expression in injured fibroblasts.
  • TNF-α induces c-Fos, which forms a complex with YY1, leading to transcriptional repression of PDGF-R-α.
  • HDAC activity, specifically involving HDAC-1, is essential for TNF-α-mediated suppression of PDGF-R-α.
  • siRNA targeting c-Fos or YY1 abrogated TNF-α's inhibitory effect on PDGF-R-α expression.

Conclusions:

  • Endogenous TNF-α paracrine activity mediates transcriptional repression of PDGF-R-α after fibroblast injury.
  • The formation of a c-Fos-YY1 complex and subsequent HDAC recruitment are critical for this repression.
  • These findings reveal a novel regulatory pathway impacting fibroblast function and potentially wound healing outcomes.

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