Yin Yang-1 inhibits vascular smooth muscle cell growth and intimal thickening by repressing p21WAF1/Cip1 transcription and p21WAF1/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

doi:10.1161/CIRCRESAHA.106.145235

Yin Yang-1 inhibits vascular smooth muscle cell growth and intimal thickening by repressing p21WAF1/Cip1 transcription and p21WAF1/Cip1-Cdk4-cyclin D1 assembly

Circ Res. 2007 Jul 20;101(2):146-55. doi: 10.1161/CIRCRESAHA.106.145235. Epub 2007 Jun 7.

Authors

Fernando S Santiago¹, 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

Affiliation

¹ Centre for Vascular Research, Department of Pathology, University of New South Wales, and Department of Haematology, The Prince of Wales Hospital, Sydney, NSW, Australia.

PMID: 17556661
DOI: 10.1161/CIRCRESAHA.106.145235

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arteries / cytology
Arteries / growth & development
Cell Line
Cyclin D
Cyclin-Dependent Kinase 4 / genetics
Cyclin-Dependent Kinase 4 / metabolism*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Cyclins / genetics
Cyclins / metabolism*
Gene Expression Regulation / physiology
Humans
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism*
Myocytes, Smooth Muscle / cytology
Myocytes, Smooth Muscle / metabolism*
Proliferating Cell Nuclear Antigen / biosynthesis
Proliferating Cell Nuclear Antigen / genetics
Protein Binding / physiology
Rabbits
Rats
Response Elements / physiology
Retinoblastoma Protein / biosynthesis
Retinoblastoma Protein / genetics
Sp1 Transcription Factor / genetics
Sp1 Transcription Factor / metabolism
Thymidine Kinase / biosynthesis
Thymidine Kinase / genetics
Transcription, Genetic / physiology
Tumor Suppressor Protein p53 / biosynthesis
Tumor Suppressor Protein p53 / genetics
Tunica Intima / cytology
Tunica Intima / growth & development*
YY1 Transcription Factor / genetics
YY1 Transcription Factor / metabolism*

Substances

CDKN1A protein, human
Cdkn1a protein, rat
Cyclin D
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Multiprotein Complexes
Proliferating Cell Nuclear Antigen
Retinoblastoma Protein
Sp1 Transcription Factor
Tumor Suppressor Protein p53
YY1 Transcription Factor
Thymidine Kinase
thymidine kinase 1
CDK4 protein, human
Cdk4 protein, rat
Cyclin-Dependent Kinase 4