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

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-Kruppel zinc finger protein Yin Yang-1 (YY1) inhibits neointima formation in human, rabbit and rat blood vessels. YY1 inhibits p(21WAF1/Cip1) transcription, prevents assembly of a p(21WAF1/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 p(21WAF1/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 p(21WAF1/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 p(21WAF1/Cip1) transcription, p(21WAF1/Cip1-) cdk4-cyclin D1 assembly and intimal thickening.