Yin Yang‐1 Inhibits Intimal Thickening by Repressing p21WAF1/Cip1 Transcription and p21WAF1/Cip1‐Cdk4‐Cyclin D1 Assembly

Abstract

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 injury‐inducible GLI‐Krüppel zinc finger protein YY1 inhibits neointima formation in human, rabbit and rat blood vessels. YY1 inhibits p21WAF1/Cip1 transcription, prevents assembly of a p21WAF1/Cip1‐cdk4‐cyclin D1 complex, and blocks downstream pRbSer249/Thr252 phosphorylation and expression of PCNA and TK‐1. Conversely, suppression of endogenous YY1 elevates levels of p21WAF1/Cip1, PCNA, pRbSer249/Thr252 and TK‐1, and increases intimal thickening. YY1 binds Sp1 and prevents its occupancy of a distinct element in the p21WAF1/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 SMCs, and an indirect repressor of p21WAF1/Cip1 transcription, p21WAF1/Cip1‐cdk4‐cyclin D1 assembly and intimal thickening.