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Gupta, S,Read, DE,Deepti, A,Cawley, K,Gupta, A,Oommen, D,Verfaillie, T,Matus, S,Smith, MA,Mott, JL,Agostinis, P,Hetz, C,Samali, A
2012
June
Cell Death & Disease
Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis
Published
()
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miR-106b-25 unfolded protein response apoptosis Bim ATF4 NRF2 UNFOLDED PROTEIN RESPONSE AMYOTROPHIC-LATERAL-SCLEROSIS ENDOPLASMIC-RETICULUM STRESS OXIDATIVE STRESS TRANSCRIPTION FACTOR MESSENGER-RNA CELL-DEATH EXPRESSION ACTIVATION DISEASE
3
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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