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

S. Gupta, D. E. Read, A. Deepti, K. Cawley, A. Gupta, D. Oommen, T. Verfaillie, S. Matus, M. A. Smith, J. L. Mott, P. Agostinis, C. Hetz, A. Samali

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

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 themiR-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 factorerythroid- 2-related factor 2). ER stress increased the activity of WT Bim 30UTR (untranslated region) construct but not the miR-106b-25 recognition site-mutated Bim 30UTR 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.

Original languageEnglish (US)
Pages (from-to)e333
JournalCell Death and Disease
Volume3
Issue number6
DOIs
StatePublished - Jun 2012

Keywords

  • ATF4
  • Bim
  • NRF2
  • apoptosis
  • miR-106b-25
  • unfolded protein response

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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