Regulation of smooth muscle cell proliferation by beta-catenin/T-cell factor signaling involves modulation of cyclin D1 and p21 expression

Helen Quasnichka, Sadie C Slater, Cressida A Beeching, Manfred Boehm, Graciela B Sala-Newby, Sarah J George

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We previously observed that stimulation of vascular smooth muscle cell (VSMC) proliferation with growth factors is associated with dismantling of cadherin junctions and nuclear translocation of beta-catenin. In this study we demonstrate directly that growth factors stimulate beta-catenin/T-cell factor (TCF) signaling in primary VSMCs. To determine whether beta-catenin/TCF signaling regulates VSMC proliferation via modulation of the beta-catenin/TCF responsive cell cycle genes, cyclin D1 and p21, we inhibited beta-catenin/TCF signaling by adenoviral-mediated over-expression of N-Cadherin, ICAT (an endogenous inhibitor of beta-catenin/TCF signaling), or a dominant negative (dn) mutant of TCF-4. N-cadherin, ICAT or dnTCF-4 over-expression significantly reduced proliferation of isolated human VSMCs by approximately 55%, 80%, and 45% respectively. Similar effects were observed in human saphenous vein medial segments where proliferation was reduced by approximately 55%. Transfection of dnTCF-4 in the ISS10 human VSMC line significantly lowered TCF and cyclin D1 reporter activity but significantly elevated p21 reporter activity, indicating regulation of these genes by beta-catenin/TCF signaling. In support of this, over-expression of N-cadherin, ICAT or dnTCF-4 in isolated human VSMCs significantly lowered levels of cyclin D1 mRNA and protein levels. In contrast, over-expression of N-Cadherin, ICAT or dnTCF4 significantly elevated p21 mRNA and protein levels. In summary, we have demonstrated that increasing N-cadherin and inhibiting beta-catenin/TCF signaling reduces VSMC proliferation, decreases the expression of cyclin D1 and increases levels of the cell cycle inhibitor, p21. We therefore suggest that the N-cadherin and beta-catenin/TCF signaling pathway is a key modulator of VSMC proliferation via regulation of these 2 beta-catenin/TCF responsive genes.

Original languageEnglish
Pages (from-to)1329-37
Number of pages9
JournalCirculation Research
Issue number12
Publication statusPublished - 8 Dec 2006


  • Aorta/cytology
  • Cell Division/physiology
  • Cells, Cultured
  • Cyclin D1/genetics
  • Cyclin-Dependent Kinase Inhibitor p21/genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Muscle, Smooth, Vascular/cytology
  • Saphenous Vein/cytology
  • Signal Transduction/physiology
  • TCF Transcription Factors/metabolism
  • Transcription, Genetic/physiology
  • Vascular Diseases/metabolism
  • beta Catenin/metabolism


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