Perk-dependent repression of mir-106b-25 cluster is required for er stress-induced apoptosis
Gupta, S ; Read, D E ; Deepti, A ; Cawley, K ; Gupta, A ; Oommen, D ; Verfaillie, T ; Matus, S ; Smith, M A ; Mott, J L ... show 3 more
Gupta, S
Read, D E
Deepti, A
Cawley, K
Gupta, A
Oommen, D
Verfaillie, T
Matus, S
Smith, M A
Mott, J L
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Publication Date
2012-06-01
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Article
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Gupta, S; Read, D E; Deepti, A; Cawley, K; Gupta, A; Oommen, D; Verfaillie, T; Matus, S; Smith, M A; Mott, J L; Agostinis, P; Hetz, C; Samali, A (2012). Perk-dependent repression of mir-106b-25 cluster is required for er stress-induced apoptosis. Cell Death and Disease 3 ,
Abstract
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 SOD1(G86R) 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. Cell Death and Disease (2012) 3, e333; doi:10.1038/cddis.2012.74; published online 28 June 2012
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Springer Nature
Publisher DOI
10.1038/cddis.2012.74
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Attribution-NonCommercial-NoDerivs 3.0 Ireland