Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis.
Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis.
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DOI：
10.1038/cddis.2012.74
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发表时间：
2012-06-28
影响因子：
9
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未折叠的蛋白反应感受器PKR样内质网状激酶(PERK)的激活可减轻内质网(ER)应激水平。相反，如果损伤太严重，内质网功能不能恢复，这个信号分支就会触发细胞凋亡。BCL-2同源3家族成员Bim在内质网应激诱导的细胞凋亡中起着至关重要的作用。然而，在内质网应激条件下控制Bim激活的调控机制还不是很清楚。在这里，我们表明miR-106b-25簇的下调有助于内质网应激诱导的细胞凋亡和Bim的上调。金丝桃素介导的光氧化内质网损伤诱导PERK依赖的细胞死亡，并导致野生型(WT)中miR-106b-25簇的miRNAs水平显著降低，但在PERK−/−MEF中没有。此外，我们还发现miR-106b-25和MCM-7(miR-106b-25的宿主基因)的表达是通过转录因子ATF4(激活转录因子4)和Nrf2(核因子-红系相关因子2)共同调节的。内质网应激增加WT Bim 3‘UTR(非翻译区)构建体的活性，但不增加识别位点突变的Bim 3’UTR构建体的活性。在WT中过表达miR-106b-25簇可以抑制内质网应激诱导的细胞死亡，但在Bim基因敲除细胞中不能提供任何进一步的保护。此外，我们发现在有症状的SOD1G86R转基因小鼠中miR-106b-25簇的水平下调。我们的结果提示，miR-106b-25簇的抑制在内质网应激介导的Bim增加和细胞凋亡中起重要作用的分子机制。
Activation of the unfolded protein response sensor PKR-like endoplasmic reticulum kinase (Perk) attenuates endoplasmic reticulum (ER) stress levels. Conversantly, if the damage is too severe and ER function cannot be restored, this signaling branch triggers apoptosis. Bcl-2 homology 3-only family member Bim is essential for ER stress-induced apoptosis. However, the regulatory mechanisms controlling Bim activation under ER stress conditions are not well understood. Here, we show that downregulation of the miR-106b-25 cluster contributes to ER stress-induced apoptosis and the upregulation of Bim. Hypericin-mediated photo-oxidative ER damage induced Perk-dependent cell death and led to a significant decrease in the levels of miRNAs belonging to miR-106b-25 cluster in wild-type (WT) but not in Perk−/− MEFs. Further, we show that expression of miR-106b-25 and Mcm-7 (host gene of miR-106b-25) is co-regulated through the transcription factors Atf4 (activating transcription factor 4) and Nrf2 (nuclear factor-erythroid-2-related factor 2). ER stress increased the activity of WT Bim 3′UTR (untranslated region) construct but not the miR-106b-25 recognition site-mutated Bim 3′UTR construct. Overexpression of miR-106b-25 cluster inhibits ER stress-induced cell death in WT but did not confer any further protection in Bim-knockdown cells. Further, we show downregulation in the levels of miR-106b-25 cluster in the symptomatic SOD1G86R transgenic mice. Our results suggest a molecular mechanism whereby repression of miR-106b-25 cluster has an important role in ER stress-mediated increase in Bim and apoptosis.
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影响因子：
16
作者：
Dehan, Elinor;Bassermann, Florian;Guardavaccaro, Daniele;Vasiliver-Shamis, Gaia;Cohen, Michael;Lowes, Kym N.;Dustin, Michael;Huang, David C. S.;Taunton, Jack;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
12.4
作者：
Ghodgaonkar, M. M.;Shah, R. G.;Shah, G. M.
通讯作者：
Shah, G. M.
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
4.8
作者：
Li, JZ;Lee, B;Lee, AS
通讯作者：
Lee, AS
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M