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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.

Authors

Helen Quasnichka

Sadie C. Slater

Cressida A. Beeching

Manfred Boehm

Graciela B. Sala-Newby

Sarah J. George



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.

Citation

Quasnichka, H., Slater, S. C., Beeching, C. A., Boehm, M., Sala-Newby, G. B., & George, S. 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), 1329-1337. https://doi.org/10.1161/01.RES.0000253533.65446.33

Journal Article Type Article
Publication Date Dec 8, 2006
Deposit Date Jan 26, 2023
Journal Circulation Research
Print ISSN 0009-7330
Electronic ISSN 1524-4571
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