NOXA contributes to the sensitivity of PERK-deficient cells to ER stress

FEBS Lett. 2012 Nov 16;586(22):4023-30. doi: 10.1016/j.febslet.2012.10.002. Epub 2012 Oct 12.

Abstract

PKR-like ER kinase (PERK) deficient mouse embryonic fibroblasts (MEFs) are hypersensitive to ER stress-induced apoptosis. However, the molecular determinants of increased sensitivity of PERK(-/-) MEFs are not clearly understood. Here we show that induction of several Unfolded Protein Response (UPR) target genes is attenuated in PERK(-/-) MEFs. We also report elevated expression of the BH3-only protein, NOXA in PERK(-/-) MEFs. Further, shRNA-mediated knockdown of NOXA rescued the hypersensitivity of PERK(-/-) MEFs to ER stress-induced apoptosis. Taken together our results suggest that compromised induction of UPR and increased NOXA expression contributes to hypersensitivity of PERK(-/-) MEFs to ER stress-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Blotting, Western
  • Caspases / metabolism
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Endoplasmic Reticulum Stress / genetics*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Gene Expression
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thapsigargin / pharmacology
  • Tunicamycin / pharmacology
  • Unfolded Protein Response / genetics
  • eIF-2 Kinase / deficiency
  • eIF-2 Kinase / genetics*

Substances

  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Tunicamycin
  • Thapsigargin
  • PERK kinase
  • eIF-2 Kinase
  • Caspases