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SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation

S Poser1, S Impey, K Trinh

  • 1Department of Pharmacology, School of Medicine, University of Washington, Seattle, 98195, USA.

The EMBO Journal
|September 16, 2000
PubMed

Insights

This study reveals a new pathway where phosphatidylinositol 3-kinase (PI3K) controls cell cycle entry. This PI3K pathway activates gene expression via SRF, crucial for growth factor-stimulated cell proliferation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Phosphatidylinositol 3-kinase (PI3K) is recognized as a key regulator in cell division, programmed cell death, and cancer development.
  • The precise mechanisms by which PI3K influences cell proliferation remain incompletely understood.
  • Mitogens initiate the cell cycle by upregulating immediate early genes (IEGs), which subsequently drive the expression of G(1) cyclins.

Purpose of the Study:

  • To elucidate the novel mechanisms by which PI3K regulates gene expression and cell cycle progression.
  • To identify the role of PI3K in mitogen-induced expression of immediate early genes, specifically c-fos.
  • To characterize a new transcriptional cascade regulated by PI3K.

Main Methods:

  • Investigated PI3K's role in gene activation using reporter assays.
  • Examined the involvement of Serum Response Factor (SRF)-dependent transcription.
  • Utilized dominant-negative PI3K and SRF mutants to assess their impact on cell cycle progression.
  • Assessed the effect of constitutively active SRF on cell cycle entry.

Main Results:

  • Discovered a novel PI3K-regulated transcriptional cascade essential for mitogen control of the c-fos immediate early gene.
  • Demonstrated that PI3K activates gene expression by transactivating SRF-dependent transcription, independent of Rho and ETS TCF pathways.
  • Showed that PI3K-mediated cell cycle progression necessitates SRF transactivation, and dominant-negative PI3K inhibits mitogen-stimulated cell cycle entry.
  • Found that dominant-interfering SRF mutants partially block mitogen-stimulated cell cycle progression but do not affect MEK-stimulated entry.
  • Confirmed that expressing constitutively active SRF is sufficient to induce cell cycle entry.

Conclusions:

  • A novel SRF-dependent mitogenic signaling cascade has been identified.
  • This pathway is critical for both PI3K and growth factor-mediated cell cycle progression.
  • The findings provide new insights into the molecular mechanisms governing cell proliferation.

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