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
| Autor: | Fernando S. Santiago, Alex Bobik, Hideto Ishii, Shahida Shafi, Manfred J. Ramirez, Levon M. Khachigian, Rohit Khurana, John Martin, Peter Kanellakis, Ian Zachary, Colin N. Chesterman, Ravinay Bhindi |
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| Rok vydání: | 2007 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Neointima Vascular smooth muscle Transcription Genetic Sp1 Transcription Factor Physiology Cyclin D Myocytes Smooth Muscle Repressor Biology Response Elements Retinoblastoma Protein Thymidine Kinase Cell Line Transcription (biology) Cyclins Proliferating Cell Nuclear Antigen Animals Humans Myocyte neoplasms Transcription factor YY1 Transcription Factor Zinc finger Cyclin-Dependent Kinase 4 Arteries Molecular biology Rats Gene Expression Regulation Multiprotein Complexes embryonic structures biology.protein Rabbits Tumor Suppressor Protein p53 biological phenomena cell phenomena and immunity Tunica Intima Cardiology and Cardiovascular Medicine Protein Binding |
| Zdroj: | Circulation Research. 101:146-155 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.106.145235 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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