title: Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis.
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.
authors: School of Medicine-Pathology, Clinical Science Institute, National University of Ireland Galway, Galway, Ireland. sanjeev.gupta@nuigalway.ie
authors: S
authors: S
authors: Gupta
authors: D E
authors: DE
authors: Read
authors: A
authors: A
authors: Deepti
authors: K
authors: K
authors: Cawley
authors: A
authors: A
authors: Gupta
authors: D
authors: D
authors: Oommen
authors: T
authors: T
authors: Verfaillie
authors: S
authors: S
authors: Matus
authors: M A
authors: MA
authors: Smith
authors: J L
authors: JL
authors: Mott
authors: P
authors: P
authors: Agostinis
authors: C
authors: C
authors: Hetz
authors: A
authors: A
authors: Samali
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D051701:Activating Transcription Factor 4; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D011518:Proto-Oncogene Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C000606776:Bcl2l11 protein, mouse; C543896:Mirn106 microRNA, mouse; C495636:Nfe2l2 protein, mouse; C000606291:Sod1 protein, mouse