Published online before print November 22, 2006, doi: 10.1161/01.RES.0000253533.65446.33
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Submitted on June 15, 2006
Revised on October 9, 2006
Accepted on October 24, 2006
Regulation of Smooth Muscle Cell Proliferation by 
-Catenin/T-Cell Factor Signaling Involves Modulation of Cyclin D1 and p21 Expression
Helen Quasnichka ;
From the Bristol Heart Institute (H.Q., S.C.S., C.A.B., G.B.S.-N., S.J.G.), Level 7, Bristol Royal Infirmary, Upper Maudlin St, BRISTOL, BS2 8HW, UK, Cardiovascular Branch (M.B.), National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
* To whom correspondence should be addressed. E-mail: s.j.george{at}bris.ac.uk.
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 
-catenin. In this study we demonstrate directly that growth factors stimulate -catenin/T-cell factor (TCF) signaling in primary VSMCs. To determine whether -catenin/TCF signaling regulates VSMC proliferation via modulation of the -catenin/TCF responsive cell cycle genes, cyclin D1 and p21, we inhibited -catenin/TCF signaling by adenoviral-mediated over-expression of N-Cadherin, ICAT (an endogenous inhibitor of -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 -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 -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 -catenin/TCF signaling pathway is a key modulator of VSMC proliferation via regulation of these 2 -catenin/TCF responsive genes.
Key words: smooth muscle • proliferation • cell cycle
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