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.; George, Sarah J.

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. © 2006 American Heart Association, Inc.

• Journal Article Type: Article
• Publication Date: Dec 8, 2006
• Deposit Date: Jan 26, 2023
• Journal: Circulation Research
• Print ISSN: 0009-7330
• Publisher: American Heart Association
• Peer Reviewed: Peer Reviewed
• Volume: 99
• Issue: 12
• Pages: 1329-1337
• DOI: https://doi.org/10.1161/01.RES.0000253533.65446.33
• Keywords: Cardiology and Cardiovascular Medicine; Physiology
• Public URL: https://uwe-repository.worktribe.com/output/10339065
• Publisher URL: https://www.ahajournals.org/doi/10.1161/01.RES.0000253533.65446.33