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, Justin L Mott, P. Agostinis, C. Hetz, A. Samali

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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)
JournalCell Death and Disease
Volume3
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Phosphotransferases
Apoptosis
Activating Transcription Factor 4
Cell Death
Down-Regulation
Untranslated Regions
Unfolded Protein Response
MicroRNAs
Transgenic Mice
Transcription Factors
Up-Regulation
Genes

Keywords

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

ASJC Scopus subject areas

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

Cite this

Gupta, S., Read, D. E., Deepti, A., Cawley, K., Gupta, A., Oommen, D., ... Samali, A. (2012). Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. Cell Death and Disease, 3(6). https://doi.org/10.1038/cddis.2012.74

Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. / Gupta, S.; Read, D. E.; Deepti, A.; Cawley, K.; Gupta, A.; Oommen, D.; Verfaillie, T.; Matus, S.; Smith, M. A.; Mott, Justin L; Agostinis, P.; Hetz, C.; Samali, A.

In: Cell Death and Disease, Vol. 3, No. 6, 01.06.2012.

Research output: Contribution to journalArticle

Gupta, S, Read, DE, Deepti, A, Cawley, K, Gupta, A, Oommen, D, Verfaillie, T, Matus, S, Smith, MA, Mott, JL, Agostinis, P, Hetz, C & Samali, A 2012, 'Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis', Cell Death and Disease, vol. 3, no. 6. https://doi.org/10.1038/cddis.2012.74
Gupta, S. ; Read, D. E. ; Deepti, A. ; Cawley, K. ; Gupta, A. ; Oommen, D. ; Verfaillie, T. ; Matus, S. ; Smith, M. A. ; Mott, Justin L ; Agostinis, P. ; Hetz, C. ; Samali, A. / Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. In: Cell Death and Disease. 2012 ; Vol. 3, No. 6.
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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.",
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AU - Deepti, A.

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AU - Gupta, A.

AU - Oommen, D.

AU - Verfaillie, T.

AU - Matus, S.

AU - Smith, M. A.

AU - Mott, Justin L

AU - Agostinis, P.

AU - Hetz, C.

AU - Samali, A.

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AB - 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.

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