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Platelet-derived growth factor stimulates Src-dependent mRNA stabilization of specific early genes in fibroblasts

Paul A Bromann1, Hasan Korkaya, Craig P Webb

  • 1Laboratory of Signal Regulation and Cancer, Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, Michigan 49503, USA.

The Journal of Biological Chemistry
|January 8, 2005
PubMed

Insights

Platelet-derived growth factor (PDGF) utilizes a specific Src family kinase (SFK) pathway to regulate gene expression. This pathway enhances messenger RNA (mRNA) stability rather than transcription, distinct from PI3K and Ras-MAPK pathways.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Expression Regulation

Background:

  • Src family kinases (SFKs) are crucial in cell signaling pathways, influencing cell growth, apoptosis, and motility.
  • SFKs are known to be essential for the mitogenic effects of platelet-derived growth factor (PDGF).
  • The precise mechanism by which SFKs mediate PDGF-stimulated gene expression remains unclear, with uncertainty regarding a discrete pathway versus general enhancement.

Purpose of the Study:

  • To investigate whether SFKs mediate PDGF-stimulated gene expression through a distinct pathway or a general enhancement mechanism.
  • To identify specific genes regulated by SFKs in response to PDGF.
  • To elucidate the role of SFKs, phosphatidylinositol 3-kinase (PI3K), and MEK1/2 in PDGF-induced gene expression.

Main Methods:

  • Treatment of quiescent NIH3T3 cells with PDGF in the presence of small molecule inhibitors for SFKs (SU6656), PI3K (LY294002), and MEK1/2 (U0126).
  • Global gene expression analysis using Affymetrix Gene-Chip arrays.
  • Validation of gene expression data through reverse transcription-PCR and ribonuclease protection assays, including nuclear run-off assays.

Main Results:

  • A specific set of immediate early genes was identified as being induced by PDGF and inhibited by the SFK inhibitor SU6656.
  • A subset of these SFK-dependent genes was induced by PDGF independently of MEK1/2 or PI3K inhibition.
  • PDGF was found to enhance mRNA stability rather than transcription rate for these SFK-dependent immediate early genes.

Conclusions:

  • PDGF regulates gene expression via an SFK-specific pathway distinct from the Ras-MAPK and PI3K pathways.
  • SFKs play a critical role in signaling gene expression by promoting mRNA stabilization in response to PDGF.
  • This study clarifies a specific mechanism of SFK-mediated gene regulation in cellular responses to growth factors.

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