title: miR-200c-SUMOylated KLF4 feedback loop acts as a switch in transcriptional programs that control VSMC proliferation.
abstract: The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue because it has major implications for the prevention of pathological vascular conditions. Using microRNA array screen, we found the expression levels of 200 unique miRNAs in hyperplasic tissues. Among them, miR-200c expression substantially was down-regulated. The objective of this work was to assess the function of miR-200c and SUMOylated Krϋppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in both cultured cells and animal models of balloon injury. Under basal conditions, we found that miR-200c inhibited the expression of KLF4 and the SUMO-conjugating enzyme Ubc9. Upon PDGF-BB treatment, Ubc9 interacted with and promoted the SUMOylation of KLF4, which allowed the recruitment of transcriptional corepressors (e.g., nuclear receptor corepressor (NCoR) and HDAC2) to the miR-200c promoter. The reduction in miR-200c levels led to increased target gene expression (e.g., Ubc9 and KLF4), which further repressed miR-200c levels and accelerated VSMC proliferation. These results demonstrate that induction of a miR-200c-SUMOylated KLF4 feedback loop is a significant aspect of the PDGF-BB proliferative response in VSMCs and that targeting Ubc9 represents a novel approach for the prevention of restenosis.
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China. Electronic address: doublezb@sina.com.
authors: Bin
authors: B
authors: Zheng
authors: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors: Michel
authors: M
authors: Bernier
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Xin-hua
authors: XH
authors: Zhang
authors: Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan.
authors: Toru
authors: T
authors: Suzuki
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Chan-quan
authors: CQ
authors: Nie
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Yong Hui
authors: YH
authors: Li
authors: Department of Urinary Surgery, Second Hospital of Hebei Medical University, Pingan Road, Shijiazhuang 050000, China.
authors: Yong
authors: Y
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Li-Li
authors: LL
authors: Song
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Hui-jing
authors: HJ
authors: Shi
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Yan
authors: Y
authors: Liu
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors: Cui-ying
authors: CY
authors: Zheng
authors: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China. Electronic address: wjk@hebmu.edu.cn.
authors: Jin-kun
authors: JK
authors: Wen
mesh_terms: D000077214:Becaplermin; D049109:Cell Proliferation; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D034622:RNA Interference; D026362:Serum Response Factor / Q000235:genetics; D058207:Sumoylation / Q000187:drug effects; D014158:Transcription, Genetic; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D056970:Co-Repressor Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D020574:Proto-Oncogene Proteins c-sis; C476858:SRF protein, human; D026362:Serum Response Factor; D000077214:Becaplermin; D056466:Histone Demethylases; C495195:KDM1A protein, human; D044763:Ubiquitin-Conjugating Enzymes; D056464:Histone Deacetylase 2; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: KLF4; Proliferation; SUMOylation; Ubc9; VSMC; miR-200c