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-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.
Santiago
Fernando S
FS
Centre for Vascular Research, Department of Pathology, University of New South Wales, and Department of Haematology, The Prince of Wales Hospital, Sydney, NSW, Australia.
Ishii
Hideto
H
Shafi
Shahida
S
Khurana
Rohit
R
Kanellakis
Peter
P
Bhindi
Ravinay
R
Ramirez
Manfred J
MJ
Bobik
Alexander
A
Martin
John F
JF
Chesterman
Colin N
CN
Zachary
Ian C
IC
Khachigian
Levon M
LM
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000254:growth & development; D002460:Cell Line; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D011817:Rabbits; D051381:Rats; D020218:Response Elements / Q000502:physiology; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D017539:Tunica Intima / Q000166:cytology / Q000254:growth & development*; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D046912:Multiprotein Complexes; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D050986:YY1 Transcription Factor; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C495900:CDK4 protein, human; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4