Cell Death and Disease
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.
Activating Transcription Factor 4, Animals, Apoptosis, Apoptosis Regulatory Proteins, Cells, Cultured, Down-Regulation, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Membrane Proteins, Mice, Mice, Transgenic, MicroRNAs, NF-E2-Related Factor 2, Proto-Oncogene Proteins, Superoxide Dismutase, eIF-2 Kinase
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Gupta, S.; Read, D. E.; Deepti, A.; Cawley, K.; Gupta, A.; Oommen, D.; Verfaillie, T.; Matus, S.; Smith, Mary A.; Mott, Justin L.; Agostinis, P.; Hetz, C.; and Samali, A., "Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis." (2012). Journal Articles: Biochemistry & Molecular Biology. 26.