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(Circulation Research. 2007;101:146.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Yin Yang-1 Inhibits Vascular Smooth Muscle Cell Growth and Intimal Thickening by Repressing p21^WAF1/Cip1 Transcription and p21^WAF1/Cip1-Cdk4-Cyclin D1 Assembly

Fernando S. Santiago^*, Hideto Ishii^*, Shahida Shafi, Rohit Khurana, Peter Kanellakis, Ravinay Bhindi, Manfred J. Ramirez, Alexander Bobik, John F. Martin, Colin N. Chesterman, Ian C. Zachary, Levon M. Khachigian

From the Centre for Vascular Research, Department of Pathology, University of New South Wales, and Department of Haematology, The Prince of Wales Hospital (F.S.S., H.I., R.B. C.N.C., L.M.K.), Sydney, NSW, Australia; Centre for Cardiovascular Biology and Medicine, BHF Laboratories, Department of Medicine, University College London (S.S., R.K., M.J.R., J.F.M., I.C.Z.), United Kingdom; Cell Biology Laboratory (P.K., A.B.), Baker Heart Research Institute, Australia.

Correspondence to Levon M. Khachigian, PhD, DSc, Centre for Vascular Research, Department of Pathology, The University of New South Wales, Sydney NSW 2052 Australia. E-mail L.Khachigian{at}unsw.edu.au

Vascular injury initiates a cascade of phenotype-altering molecular events. Transcription factor function in this process, particularly that of negative regulators, is poorly understood. We demonstrate here that the forced expression of the injury-inducible GLI-Krüppel zinc finger protein Yin Yang-1 (YY1) inhibits neointima formation in human, rabbit and rat blood vessels. YY1 inhibits p21^WAF1/Cip1 transcription, prevents assembly of a p21^WAF1/Cip1-cdk4-cyclin D1 complex, and blocks downstream pRb^{Ser249/Thr252} phosphorylation and expression of PCNA and TK-1. Conversely, suppression of endogenous YY1 elevates levels of p21^WAF1/Cip1, PCNA, pRb^{Ser249/Thr252} and TK-1, and increases intimal thickening. YY1 binds Sp1 and prevents its occupancy of a distinct element in the p21^WAF1/Cip1 promoter without YY1 itself binding the promoter. Additionally, YY1 induces ubiquitination and proteasome-dependent degradation of p53, decreasing p53 immunoreactivity in the artery wall. These findings define a new role for YY1 as both an inducer of p53 instability in smooth muscle cells, and an indirect repressor of p21^WAF1/Cip1 transcription, p21^WAF1/Cip1-cdk4-cyclin D1 assembly and intimal thickening.

Key Words: gene expression • arterial injury • intimal thickening • vascular biology

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The Balance of Power: The Law of Yin and Yang in Smooth Muscle Cell Fate: Is YY1 a Vascular Protector?

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Circ. Res. 2007 101: 111-113. [Full Text] [PDF]

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