dc.contributor.author | Gupta, Sanjeev | |
dc.contributor.author | Read, D.E. | |
dc.contributor.author | Deepti, A. | |
dc.contributor.author | Cawley, K. | |
dc.contributor.author | Gupta, A. | |
dc.contributor.author | Oommen, D. | |
dc.contributor.author | Samal, Afshin | |
dc.date.accessioned | 2012-07-09T10:01:38Z | |
dc.date.available | 2012-07-09T10:01:38Z | |
dc.date.issued | 2012 | |
dc.identifier.citation | S Gupta, DE Read, A Deepti, K Cawley, A Gupta, D Oommen, T Verfaillie4, S Matus, MA Smith, JL Mott, (2012) 'Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis'. Cell Death & Disease, . | en_US |
dc.identifier.uri | http://hdl.handle.net/10379/2901 | |
dc.description.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 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. | en_US |
dc.format | application/pdf | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Cell Death & Disease | en |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 Ireland | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/ie/ | |
dc.subject | miR-106b-25 | en_US |
dc.subject | Unfolded protein response | en_US |
dc.subject | Apoptosis | en_US |
dc.subject | Bim | en_US |
dc.subject | ATF4 | en_US |
dc.subject | NRF2 | en_US |
dc.title | Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis | en_US |
dc.type | Article | en_US |
dc.date.updated | 2012-07-03T10:56:05Z | |
dc.description.peer-reviewed | peer-reviewed | |
dc.contributor.funder | SFI | |
dc.contributor.funder | HRB | |
dc.internal.rssid | 1906704 | |
dc.local.contact | Sanjeev Gupta, Pathology, School Of Medicine, Nui Galway. 544488 Email: sanjeev.gupta@nuigalway.ie | |
dc.local.copyrightchecked | Yes | |
dc.local.version | ACCEPTED | |
nui.item.downloads | 531 | |