Smad Pathway-Specific Transcriptional Regulation of the Cell Cycle Inhibitor p21(WAF1/Cip1)

J Cell Physiol. 2005 Jul;204(1):260-72. doi: 10.1002/jcp.20304.

Abstract

Transforming growth factor-beta (TGF-beta) inhibits epithelial cell growth, in part via transcriptional induction of the cell cycle inhibitor p21(WAF1/Cip1) (p21). We show that bone morphogenetic protein (BMP)-7 induces higher p21 expression than TGF-beta1 in various epithelial cells. Despite this, BMP-7 only weakly suppresses epithelial cell proliferation, as Id2, a cell cycle-promoting factor, becomes concomitantly induced by BMP-7. Signaling studies with all type I receptors of the TGF-beta superfamily show that BMP receptors induce higher p21 expression than TGF-beta/activin receptors. Smad4 is essential for p21 regulation by all receptor pathways. Based on the previously known ability of c-Myc to block p21 expression and epithelial growth arrest in response to TGF-beta1, we demonstrate that ectopic c-Myc expression can abrogate Smad-mediated p21 induction by all TGF-beta and BMP receptors. Furthermore, p21 induction by all receptor pathways can be blocked by the natural inhibitors of the TGF-beta superfamily. Smad7 inhibits all pathways whereas Smad6 selectively inhibits the BMP pathways. The observed pathway specificity reflects the efficiency by which BMP Smads, compared to TGF-beta Smads, transactivate the p21 promoter. In addition, BMP-specific Smads, Smad1, Smad5, and especially Smad8, induce endogenous p21 mRNA and protein levels, while they fail to induce epithelial growth inhibition when compared to TGF-beta receptor-phosphorylated Smads (R-Smads), Smad2 and Smad3. Thus, p21 is a common target of all TGF-beta superfamily pathways. However, the ability of TGF-beta superfamily members to induce cell growth arrest depends on the regulation of additional gene targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins / pharmacology
  • Cell Cycle Proteins / genetics*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line, Transformed
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins / metabolism*
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / physiology*
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic / physiology
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Smad5 Protein
  • Smad7 Protein
  • Smad8 Protein
  • Trans-Activators / metabolism*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta1

Substances

  • BMP7 protein, human
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • MYC protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins c-myc
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • SMAD3 protein, human
  • SMAD4 protein, human
  • SMAD5 protein, human
  • SMAD7 protein, human
  • SMAD8 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Smad5 Protein
  • Smad7 Protein
  • Smad8 Protein
  • TGFB1 protein, human
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1