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Inhibition of p27Kip1 gene transcription by mitogens

Tapan K Bagui1, Dongming Cui, Sangita Roy

  • 1Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Cell Cycle (Georgetown, Tex.)
|January 23, 2009
PubMed

Insights

Platelet-derived growth factor (PDGF) and other mitogens reduce p27(Kip1) gene expression. This process involves c-Myc mediating PDGF

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Gene Regulation

Background:

  • Mitogens, such as platelet-derived growth factor (PDGF), play crucial roles in cell proliferation.
  • The cell cycle inhibitor p27(Kip1) is a key regulator of cell cycle progression.
  • Understanding how mitogens regulate p27(Kip1) is vital for comprehending cell growth control.

Purpose of the Study:

  • To investigate the molecular mechanisms by which PDGF reduces p27(Kip1) expression in mouse fibroblasts.
  • To determine the role of c-Myc in mediating PDGF's inhibitory effects on the p27(Kip1) promoter.
  • To explore whether similar mechanisms apply to other mitogens, like interleukin-2 (IL-2), in different cell types.

Main Methods:

  • Deletion analysis of the p27(Kip1) promoter.
  • Chromatin immunoprecipitation (ChIP) assays to assess protein-DNA interactions.
  • Gene expression analysis of p27(Kip1) and c-Myc in response to mitogens and inhibitors.
  • Ectopic expression of c-Myc in fibroblasts.

Main Results:

  • PDGF reduces p27(Kip1) promoter activity and mRNA abundance in fibroblasts, requiring protein synthesis and histone deacetylase activity.
  • PDGF upregulates c-Myc expression, which inhibits p27(Kip1) promoter activity.
  • c-Myc interacts with the same region of the p27(Kip1) promoter targeted by PDGF.
  • Mitogens like concanavalin A and IL-2 also reduce p27(Kip1) mRNA abundance in splenocytes and T cells, respectively.
  • IL-2-mediated reduction in T cells requires Akt activity, unlike the PDGF effect in fibroblasts.

Conclusions:

  • c-Myc mediates the inhibitory effect of PDGF on the p27(Kip1) promoter in mouse fibroblasts.
  • Mitogens can repress p27(Kip1) gene transcription through diverse mechanisms in various cell types.
  • These findings elucidate novel pathways regulating cell cycle inhibitor expression during mitogenic stimulation.

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