HDAC2 phosphorylation-dependent KIf5 deacetylation and RARa acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs  

作　　者：Bin Zheng Mei Han Ya-nan Shu Ying-jie Li Sui-bing Miao Xin-hua Zhang Hui-jing Shi Tian Zhang Jin-kun Wen 

机构地区：[1]Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, No. 361, Zhongshan East Road, Shij＇iazhuang 050017, China

出　　处：《Cell Research》2011年第10期1487-1508,共22页细胞研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China （90919035, 30971457, 30871272） and the Hebei Natural Science Foundation of China （C2007000831, C2009001541 ）.

摘　　要：proliferation of vascular smooth muscle cells （VSMCs） occurs in hypertension, atherosclerosis and restenosis after angioplasty, leading to pathophysiological vascular remodeling. As an important growth arrest gene, p21 plays critical roles in vascular remodeling. Regulation of p21 expression by retinoic acid receptor （RAR） and its ligand has important implications for control of pathological vascular remodeling. Nevertheless, the mechanism of RAR-mediated p21 expression in VSMCs remains poorly understood. Here, we show that, under basal conditions, RARa forms a complex with histone deacetylase 2 （HDAC2） and Kriippel-like factor 5 （KlfS） at the p21 promoter to inhibit its expression. Upon RARa agonist stimulation, HDAC2 is phosphorylated by CK2a. Phosphorylation of HDAC2, on the one hand, promotes its dissociation from RARa, thus allowing the liganded-RARa to interact with co-activators; on the other hand, it increases its interaction with KlfS, thus leading to deacetylation of KlfS. Deacetylation of Klf5 facilitates its dissociation from the p21 promoter, relieving its repressive effect on the p21 promoter. Interference with HDAC2 phosphorylation by either CK2a knockdown or the use of phosphorylation-deficient mutant of HDAC2 prevents the dissociation of Klf5 from the p21 promoter and impairs RAR agonist-induced p21 activation. Our results reveal a novel mechanism involving a phosphorylation-deacetylation cascade that functions to remove the basal repression complex from the p21 promoter upon RAR agonist treatment, allowing for optimum agonist- induced p21 expression.

关 键 词：vascular smooth muscle cells Kruppel-like factor 5 retinoic acid receptor a P21 gene expression signal transduction 

分 类 号：Q463[生物学—生理学] Q2