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Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21(WAF1/Cip1)

Katerina Pardali1, Marcin Kowanetz, Carl-Henrik Heldin

  • 1Ludwig Institute for Cancer Research, Uppsala, Sweden.

Journal of Cellular Physiology
|February 4, 2005
PubMed

Insights

Bone morphogenetic protein-7 (BMP-7) and transforming growth factor-beta1 (TGF-beta1) both induce the cell cycle inhibitor p21, but only TGF-beta1 effectively halts epithelial cell growth. BMP-7

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Transforming growth factor-beta (TGF-beta) inhibits epithelial cell proliferation by inducing the cell cycle inhibitor p21(WAF1/Cip1) (p21).
  • Bone morphogenetic protein (BMP)-7 also induces p21 expression in epithelial cells, but its effect on proliferation is weaker than TGF-beta1.
  • The differential effects of BMP-7 and TGF-beta1 on cell proliferation are partly due to the induction of Id2, a cell cycle-promoting factor, by BMP-7.

Purpose of the Study:

  • To investigate the role of BMP-7 and TGF-beta1 in regulating epithelial cell growth and p21 expression.
  • To compare the signaling pathways activated by BMP and TGF-beta receptors in controlling p21 expression and cell proliferation.
  • To elucidate the mechanisms underlying the differential effects of BMP and TGF-beta on epithelial cell cycle control.

Main Methods:

  • Epithelial cell culture and treatment with TGF-beta1 and BMP-7.
  • Quantitative analysis of p21 and Id2 mRNA and protein expression.
  • Analysis of Smad protein activation and nuclear translocation.
  • Reporter assays to assess p21 promoter activity.
  • Overexpression of c-Myc and Smad7/Smad6 to modulate signaling pathways.

Main Results:

  • BMP-7 induced higher p21 expression than TGF-beta1 in various epithelial cells, yet only weakly suppressed proliferation due to concomitant Id2 induction.
  • All TGF-beta superfamily type I receptors, particularly BMP receptors, induced p21 expression, with Smad4 being essential for this regulation.
  • Ectopic c-Myc expression abrogated Smad-mediated p21 induction by all TGF-beta superfamily receptors, while Smad7 inhibited all pathways and Smad6 selectively inhibited BMP pathways.
  • BMP-specific Smads (Smad1, Smad5, Smad8) induced p21 mRNA and protein but failed to inhibit epithelial growth, unlike TGF-beta receptor-phosphorylated Smads (Smad2, Smad3).

Conclusions:

  • p21 is a common transcriptional target for all TGF-beta superfamily signaling pathways.
  • The ability of TGF-beta superfamily members to induce epithelial cell growth arrest is dependent on the regulation of additional gene targets beyond p21.
  • Differential regulation of downstream targets, such as Id2, and the specific Smad proteins involved determine the ultimate effect on cell proliferation.

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