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Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis

ARAN - Access to Research at NUI Galway

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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.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

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