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Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta

Marcin Kowanetz1, Ulrich Valcourt, Rosita Bergström

  • 1Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden.

Molecular and Cellular Biology
|May 4, 2004
PubMed

Insights

Transforming growth factors beta (TGF-betas) and bone morphogenetic proteins (BMPs) use Smad4 to control cell growth and differentiation. Opposing regulation of Id genes by TGF-betas and BMPs dictates cell fate decisions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Transforming growth factors beta (TGF-betas) inhibit epithelial cell growth and induce epithelial-mesenchymal transition (EMT).
  • Bone morphogenetic proteins (BMPs) have minimal effects on epithelial cell growth and do not induce EMT.
  • Smad4 is a key signaling mediator for both TGF-beta and BMP pathways.

Purpose of the Study:

  • To investigate the role of Smad4 in mediating TGF-beta and BMP signaling in epithelial cells.
  • To identify genes regulated by TGF-beta and BMP pathways through Smad4.
  • To elucidate the opposing roles of Id2 and Id3 in mediating cellular responses to TGF-beta and BMP.

Main Methods:

  • Stimulation of Smad4-deficient epithelial cells with TGF-beta 1 or BMP-7.
  • Analysis of Smad4-deficient and Smad4-expressing cells.
  • cDNA microarray analysis to identify gene expression changes.
  • Ectopic expression and knockdown of Id2 and Id3 genes.

Main Results:

  • 173 Smad4-dependent genes responsive to TGF-beta or BMP were identified.
  • Id2 and Id3 were oppositely regulated by TGF-beta (repression) and BMP (induction).
  • Ectopic Id2/Id3 expression conferred resistance to TGF-beta-induced growth inhibition and EMT.
  • Id2/Id3 knockdown sensitized cells to BMP, causing growth inhibition and transdifferentiation.

Conclusions:

  • Id genes act as critical mediators sensing Smad signals to control epithelial cell proliferation and differentiation.
  • Opposing regulation of Id genes by TGF-betas and BMPs determines cell fate decisions.
  • Id genes create a nuclear environment that dictates cellular responses to growth factors.

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