Yin Yang-1 inhibits vascular smooth muscle cell growth and intimal thickening by repressing p21WAF1/Cip1 transcription and p21WAF1/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-Krueppel 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.
Mesh Terms:
Animals, Arteries, Cell Line, Cyclin D, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, Gene Expression Regulation, Humans, Multiprotein Complexes, Myocytes, Smooth Muscle, Proliferating Cell Nuclear Antigen, Protein Binding, Rabbits, Rats, Response Elements, Retinoblastoma Protein, Sp1 Transcription Factor, Thymidine Kinase, Transcription, Genetic, Tumor Suppressor Protein p53, Tunica Intima, YY1 Transcription Factor
Circ. Res.
Date: Jul. 20, 2007
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