miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway.
miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway.
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miR-34a 通过 PDGFR-β/Ras-MAPK 信号通路调节系膜细胞增殖
DOI：
10.1007/s00018-014-1599-y
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发表时间：
2014-10
影响因子：
8
通讯作者：
Chen, Xiangmei
中科院分区：
文献类型：
--
作者：
Chen, Dapeng;Li, Ying;Mei, Yan;Geng, Wenjia;Yang, Jurong;Hong, Quan;Feng, Zhe;Cai, Guangyan;Zhu, Hanyu;Shi, Suozhu;Bai, Xue-Yuan;Chen, Xiangmei
肾小球肾炎的主要病理特征是弥漫性系膜细胞增殖。MIR-34a与多种器官和癌细胞的增殖有关。然而，miR-34a在肾脏增生性疾病中的作用尚不清楚。因此，本研究旨在阐明miR-34a调控肾小球系膜细胞增殖的机制。采用定量RT-PCR方法检测抗Thy1系膜增殖性肾炎大鼠模型不同时间点miR-34a的表达水平。测定体外培养的大鼠肾小球系膜细胞(RMCs)的细胞增殖率和细胞周期变化。提示在抗Thy1肾炎模型中miR-34a的表达与细胞增殖程度呈负相关。MIR-34a可延长RMC的G0/G1期，抑制细胞增殖。双荧光素酶分析结果表明，在血小板衍生生长因子受体-β(PDGFR-β)的3‘非编码区有miR-34a的结合位点。MIR-34a可以在转录后水平抑制PDGFR-β蛋白的表达，抑制RAS/MAPK信号通路，下调G0/G1期细胞周期蛋白的表达，如细胞周期蛋白D1、CDK4/CDK6。此外，miR-34a还可能通过直接靶向Cyclin E和CDK2来抑制RMC的增殖。MIR-34a抑制外源性刺激诱导的系膜细胞增殖。在抗Thy-1肾炎大鼠模型中，磷酸化PDGFR-β及其信号通路下游重要分子磷酸化β的表达水平显著升高。这些结果提示，miR-34a可能通过直接抑制PDGFR-β、MEK1、细胞周期蛋白Cyclin E和CDK2的表达来调控系膜细胞的增殖。
The main pathological characteristic of glomerulonephritis is diffuse mesangial cell proliferation. MiR-34a is associated with the proliferation of various organs and cancer cells. However, the role of miR-34a in renal proliferation diseases is not clear. Therefore, this study aimed to elucidate the mechanism of miR-34a in the regulation of renal mesangial cell proliferation. The miR-34a expression level at different time points in an anti-Thy1 mesangial proliferative nephritis rat model was determined by qRT-PCR. The cell proliferation rate and cell cycle changes were measured in the in vitro cultured rat mesangial cells (RMCs). Our results suggested that miR-34a expression was negatively correlated with the degree of cell proliferation in the anti-Thy1 nephritis model. MiR-34a could extend the G0/G1 phase and block cell proliferation in RMCs. Dual-luciferase assay results showed that there were binding sites of miR-34a at 3′-UTR of platelet-derived growth factor receptor-β (PDGFR-β). MiR-34a can inhibit PDGFR-β protein expression at a post-transcriptional level, suppress Ras/MAPK signaling pathways, and down-regulate expression of cell cycle proteins at the G0/G1 phase, such as cyclin D1, CDK4/CDK6. In addition, miR-34a may also inhibit RMC proliferation by directly targeting cyclin E and CDK2. MiR-34a inhibits exogenous stimuli-induced proliferation of mesangial cells. Expression levels of phospho-PDGFR-β and phospho-MEK1 (an important downstream molecule in PDGFR-β-induced signaling pathway) were significantly increased in the anti-Thy-1 nephritis rat model. These results suggest that miR-34a may regulate RMC proliferation by directly inhibiting expressions of PDGFR-β, MEK1, and cell cycle proteins, cyclin E and CDK2.
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DOI：
10.4161/cc.9.6.10987
发表时间：
2010-03-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Guessous F;Zhang Y;Kofman A;Catania A;Li Y;Schiff D;Purow B;Abounader R
通讯作者：
Abounader R
影响因子：
13.6
作者：
Lang, S;Hartner, A;Schöcklmann, HO
通讯作者：
Schöcklmann, HO
影响因子：
6.1
作者：
Li, PKT;Ho, KKL;Lai, FMM
通讯作者：
Lai, FMM
影响因子：
6.1
作者：
Bokemeyer, Dirk;Panek, Darius;Ostendorf, Tammo
通讯作者：
Ostendorf, Tammo
影响因子：
19.6
作者：
Khwaja, A.;Sharpe, C. C.;Hendry, B. M.
通讯作者：
Hendry, B. M.