Regulation of smooth muscle cell proliferation by β-Catenin/T-Cell factor signaling involves modulation of Cyclin D1 and p21 Expression

Quasnichka, Helen, Slater, Sadie C., Beeching, Cressida A., Boehm, Manfred, Sala-Newby, Graciela B. and George, Sarah J. 2006. Regulation of smooth muscle cell proliferation by β-Catenin/T-Cell factor signaling involves modulation of Cyclin D1 and p21 Expression. Circulation Research 99 (12) , pp. 1329-1337. 10.1161/01.RES.0000253533.65446.33

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Abstract

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 β-catenin. In this study we demonstrate directly that growth factors stimulate β-catenin/T-cell factor (TCF) signaling in primary VSMCs. To determine whether β-catenin/TCF signaling regulates VSMC proliferation via modulation of the β-catenin/TCF responsive cell cycle genes, cyclin D1 and p21, we inhibited β-catenin/TCF signaling by adenoviral-mediated over-expression of N-Cadherin, ICAT (an endogenous inhibitor of β-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 β-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 β-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 β-catenin/TCF signaling pathway is a key modulator of VSMC proliferation via regulation of these 2 β-catenin/TCF responsive genes.

Item Type:	Article
Date Type:	Publication
Schools:	Biosciences
Publisher:	American Heart Association
ISSN:	0009-7330
Last Modified:	11 Mar 2023 02:06
URI:	https://orca.cardiff.ac.uk/id/eprint/134979

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