title: SUMOylation of KLF4 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 due to its major implications for the prevention of pathological vascular conditions. The objective of this work was to assess the function of small ubiquitin-like modifier (SUMO)ylated Krϋppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in cultured cells and in animal models with balloon injury. We found that under basal conditions, binding of non-SUMOylated KLF4 to p300 activated p21 (p21(WAF1/CIP1))transcription, leading to VSMC growth arrest. PDGF-BB promoted the interaction between Ubc9 and KLF4 and the SUMOylation of KLF4, which in turn recruited transcriptional corepressors to the p21 promoter. The reduction in p21 enhanced VSMC proliferation. Additionally, the SUMOylated KLF4 did not affect the expression of KLF4, thereby forming a positive feedback loop enhancing cell proliferation. These results demonstrated that SUMOylated KLF4 plays an important role in cell proliferation by reversing the transactivation action of KLF4 on p21 induced with PDGF-BB.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Chan-Juan
authors.initials: CJ
authors.lastname: Nie
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China; Hebei Center for Disease Control and Prevention, Shijiazhuang 050000, China.
authors.forename: Yong Hui
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Yin
authors.affiliation: Department of Urinary Surgery, Second Hospital of Hebei Medical University, Pingan Road, Shijiazhuang 050000, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Hui-Jing
authors.initials: HJ
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Cui-Ying
authors.initials: CY
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Third Hospital of Shijiazhuang, Shijiazhuang 050000, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China. Electronic address: doublezb@hebmu.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China. Electronic address: wjk@hebmu.edu.cn.
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Wen
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology; D017207:Rats, Sprague-Dawley; D058207:Sumoylation; D014158:Transcription, Genetic; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D044763:Ubiquitin-Conjugating Enzymes
keywords: KLF4; Proliferation; SUMOylation; Ubc9; VSMC