Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells

Gordon P. Meares, Marjelo A. Mines, Eleonore Beurel, Tae Yeon Eom, Ling Song, Anna A. Zmijewska, Richard S Jope

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress, often resulting from cellular accumulation of misfolded proteins, occurs in many neurodegenerative disorders, in part because of the relatively long lifetime of neurons. Excessive accumulation of misfolded proteins activates the unfolded protein response (UPR) that dampens protein synthesis and promotes removal of misfolded proteins to support survival of ER-stressed cells. However, the UPR also initiates apoptotic signaling to kill cells if recovery is not achieved. Thus, there is much interest in identifying determinants of the life-death switch and interventions that promote recovery and survival. One intervention that has consistently been shown to protect cells from ER stress-induced apoptosis is application of inhibitors of glycogen synthase kinase-3 (GSK3). Therefore, we examined where in the UPR pathway GSK3 inhibitors intercede to impede signaling towards apoptosis. Apoptosis following UPR activation can be mediated by activation of two transcription factors, ATF4 and ATF6, that activate expression of the death-inducing transcription factor C/EBP homologous protein (CHOP/GADD153) following ER stress. We found that ER stress activated ATF6 and ATF4, but these responses were not inhibited by pretreatment with GSK3 inhibitors. However, inhibition of GSK3 effectively reduced the expression of CHOP, and this was apparent in several types of neural-related cells and was evident after application of several structurally diverse GSK3 inhibitors. Therefore, reduction of CHOP activation provides one mechanism by which inhibitors of GSK3 are capable of shifting cell fate towards survival instead of apoptosis following ER stress.

Original languageEnglish
Pages (from-to)1621-1628
Number of pages8
JournalExperimental Cell Research
Volume317
Issue number11
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Endoplasmic Reticulum Stress
Unfolded Protein Response
Apoptosis
Activating Transcription Factor 6
Activating Transcription Factor 4
Transcription Factor CHOP
Protein Unfolding
Proteins
Endoplasmic Reticulum
Neurodegenerative Diseases
Transcription Factors
Neurons

Keywords

  • CHOP
  • ER stress
  • GADD153
  • Glycogen synthase kinase-3
  • Unfolded protein response

ASJC Scopus subject areas

  • Cell Biology

Cite this

Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells. / Meares, Gordon P.; Mines, Marjelo A.; Beurel, Eleonore; Eom, Tae Yeon; Song, Ling; Zmijewska, Anna A.; Jope, Richard S.

In: Experimental Cell Research, Vol. 317, No. 11, 01.07.2011, p. 1621-1628.

Research output: Contribution to journalArticle

Meares, Gordon P. ; Mines, Marjelo A. ; Beurel, Eleonore ; Eom, Tae Yeon ; Song, Ling ; Zmijewska, Anna A. ; Jope, Richard S. / Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells. In: Experimental Cell Research. 2011 ; Vol. 317, No. 11. pp. 1621-1628.
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