Nie Chan-Juan, Li Yong Hui, Zhang Xin-Hua, Wang Zhi-Peng, Jiang Wen, Zhang Yu, Yin Wei-Na, Zhang Yong, Shi Hui-Jing, Liu Yan, Zheng Cui-Ying, Zhang Jing, Zhang Guo-Liang, Zheng Bin, Wen Jin-Kun
Department of Biochemistry and Molecular Biology, Hebei Medical University, Zhongshan East Road, Shijiazhuang 050017, China.
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.
Exp Cell Res. 2016 Mar 1;342(1):20-31. doi: 10.1016/j.yexcr.2016.03.001. Epub 2016 Mar 2.
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.
血管平滑肌细胞（VSMC）增殖的调控是一个重要问题，因为它对预防病理性血管疾病具有重要意义。本研究的目的是评估小泛素样修饰物（SUMO）化的 Kruppel 样转录因子 4（KLF4）在培养细胞和球囊损伤动物模型中对 VSMC 增殖调控的作用。我们发现，在基础条件下，未被 SUMO 化的 KLF4 与 p300 结合可激活 p21（p21（WAF1/CIP1））转录，导致 VSMC 生长停滞。血小板衍生生长因子-BB（PDGF-BB）促进泛素结合酶 9（Ubc9）与 KLF4 之间的相互作用以及 KLF4 的 SUMO 化，这反过来又将转录共抑制因子招募到 p21 启动子上。p21 的减少增强了 VSMC 的增殖。此外，SUMO 化的 KLF4 不影响 KLF4 的表达，从而形成一个增强细胞增殖的正反馈环。这些结果表明，SUMO 化的 KLF4 通过逆转 KLF4 对 PDGF-BB 诱导的 p21 的反式激活作用，在细胞增殖中发挥重要作用。
